JP2007204458A - Three-ring heterocyclic compound having antifungal action - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound expressing specifically or selectively an antifungal action to a pathogenic fungus such as a genus Candida based on an action mechanism called 1,6-β-glucan synthesis inhibition. <P>SOLUTION: This antifungal component contains a compound represented by formula (I) (wherein R<SP>1</SP>represents a nitrogen-containing heterocyclic group or a group having a basic substituent group, the structural part containing A represents a six-membered aromatic ring which may have 1-3 nitrogen atoms), its salts, or their hydrates. For example, in case if X is oxygen, A is a pyridine ring, R<SP>1</SP>is a dimethylamino pyrrolidyl group, R<SP>2</SP>is a phenyl group, R<SP>3</SP>is a methyl group, R<SP>4</SP>is a nitrile group, etc., it shows high antifungal activity. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a compound having an antifungal action against pathogenic fungi, a salt thereof, or a solvate thereof (including a hydrate). Moreover, it is related with the antifungal agent containing these.

Fungi are known to cause various diseases by infecting humans, animals, plants and the like. For example, in addition to causing superficial mycosis on the keratinized layer of human skin, keratinized tissues such as nails and hair, and mucosal epithelium such as oral cavity, deep skin fungi also against skin tissue located deep from the body surface Cause deep mycosis in deep tissues such as the esophagus, internal organs, and brain. The main pathogenic fungi that infect humans and cause deep mycosis are Candida, Cryptococcus, Aspergillus, etc., and superficial mycosis infects the skin, oral cavity, vagina, etc. Candida spp., Ringworm that infects the skin of hands and feet, etc. are considered to be the main ones. Various other fungi exist and are thought to infect animals and plants.
Due to the rapid progress of research and development on antibiotics and chemotherapeutic drugs since 1950, and their widespread use, many therapeutic drugs for bacterial infections have been developed. Similarly, great efforts have been made toward the development of antifungal drugs, but compared to the development of antibacterial chemotherapeutic agents, there are few compounds currently in clinical use. On the other hand, the use of compromised hosts with reduced immunity due to the frequent use of antibacterial drugs (antibiotics and chemotherapeutic agents) in medical practice, malignant tumors, leukemia, organ and bone marrow transplantation, and acquired immune deficiency syndrome Due to the increase, deep mycosis has increased in recent years and has become a problem.

  The main antifungal agents currently used in clinical settings include polyene macrolides, fluoropyrimidines, and azoles. In the treatment of superficial mycosis, it is mainly used as a topical medicine, and various azole drugs, polyene macrolide nystatin, griseofulvin, terbinafine hydrochloride, butenafine hydrochloride, amorolfine hydrochloride, etc. are used. Yes. On the other hand, amphotericin B, which is a polyene macrolide, has a wide antibacterial spectrum and is highly effective in the treatment of deep mycosis, which has been increasing in recent years, but has a problem in terms of toxicity (side effects). Furthermore, flucytosine, which is a fluoropyrimidine, has low toxicity but easily causes fungal resistance. As described above, there are very few drugs currently used for the treatment of deep mycosis that have high medical satisfaction from the viewpoint of antibacterial spectrum, efficacy, safety and the like. Furthermore, fluconazole, which is particularly frequently used among these anti-deep fungi, is less susceptible to pathogenic fungi such as Candida glabrata, Candida tropicalis, Candida crusei, etc. Bacteria are also emerging. Therefore, there is a long-awaited clinical antifungal drug that overcomes these problems.

On the other hand, for the development of mycosis therapy in recent years and the development of new antifungal agents, a test method for scientific evaluation of usefulness has been established, which is more effective in combination with the progress of research on the mechanism of action. And safe drug development is desired. From the viewpoint of overcoming the problem of resistant bacteria, development of antifungal agents having a novel mechanism of action is also awaited.
Furthermore, because of safety issues, since fungi are different from bacteria (prokaryotic cells) and are eukaryotic cells similar to humans, compounds that specifically (selectively) damage fungal cells will be developed. There is a need.

  Under such circumstances, synthesis of major cell wall constituents of fungi, drugs that inhibit the so-called cell wall polysaccharide synthesis system, that is, antifungal agents whose target molecules are cell wall polysaccharide synthases that exist specifically in fungi Is expected in terms of novelty and selective toxicity. As polysaccharides constituting the fungal cell wall, β-glucan, chitin or chitosan, and mannan are known. Of these, β-glucan, which is the main component of the fungal cell wall, is 1,3-β-glucan. And 1,6-β-glucan.

Examples of 1,3-β-glucan synthase inhibitors include papracandins (Non-patent Document 1), echinocandins (Non-patent Document 2), pneumocandins (Non-patent Document 3), and acreasins (non-patent documents). Reference 4) has been reported. In recent years, Caspofungin (Non-Patent Document 5), Mikafungin (Non-Patent Document 6) and the like have been developed and marketed. However, all of these are only injections, and a novel antifungal agent effective even for oral administration is desired.
A tricyclic imidazo [1,2-a] pyridine derivative has been reported as a 1,6-β-glucan synthase inhibitor (Patent Document 1). There is a need to develop 1,6-β-glucan synthase inhibitors with spectrum.

  On the other hand, as pyridine derivatives having a bicyclic skeleton, imidazopyridine, triazolopyridine, pyrazolopyridine and its derivatives are known to have pharmacological activity in a very wide range of regions, and imidazopyrimidine and pyrazolopyridine are known. There are reports that pyrimidine derivatives show antifungal action against fungi causing plant diseases (Patent Documents 2 and 3 and Non-Patent Document 7).

International Publication No. 2003/064422 Pamphlet International Publication 2003/022850 Pamphlet International Publication No. 2005/077948 Pamphlet Journal of Antibiotics, 36, 1539 (1983) Journal of Medicinal Chemistry, 38, 3271 (1995) Journal of Antibiotics, 45, 1875 (1992) Journal of Biochemistry, Volume 105, 606 (1989) Journal of Medicinal Chemistry, 37, 222 (1994) Journal of Antibiotics, Vol. 52, p. 674 (1999) Journal of Medicinal Chemistry, Vol. 18, page 1253 (1975)

  An object of the present invention is to provide a compound capable of specifically or selectively expressing an antifungal action based on an action mechanism of 1,6-β-glucan synthesis inhibition on pathogenic fungi such as Candida. Furthermore, it is to provide an orally administrable medicament containing such a compound, a salt thereof, or a hydrate thereof, particularly an infectious disease therapeutic agent, and further an antifungal agent.

In order to obtain a compound exhibiting antifungal activity due to inhibition of 1,6-β-glucan synthase, the present inventors conducted a search for a compound, and a living body using [ ¹⁴ C] -glucose uptake as an index. A compound exhibiting an inhibitory action on 1,6-β-glucan synthesis was found by a polymer synthesis inhibition test. Furthermore, it was verified whether a group of compounds structurally similar to the compound showed antifungal activity against pathogenic fungi. As a result, the derivative represented by formula (I) having a basic substituent as a substituent and having a skeleton such as benzofuropyridine and dibenzofuran, a salt thereof, and a solvate thereof are 1,6-β-glucan. Discovered a wide range of strong antifungal effects, with synthetic inhibition as the mechanism of action, and in particular an excellent antibacterial action against the causative bacteria of deep mycosis, especially Candida, and completed the present invention .
That is, the present invention includes the following aspects:

1. A compound represented by the following formula (I), a salt thereof, or a hydrate thereof:

[Wherein R ¹ is
A saturated or partially saturated 4- to 8-membered nitrogen-containing heterocyclic group containing 1 or 2 nitrogen atoms (where, when there is only 1 nitrogen atom, this nitrogen atom is the binding site to the mother nucleus) And an alkyl group having 1 to 6 carbon atoms may be substituted on the nitrogen atom.)
Or as a basic substituent
(1) an amino group,
(2) an alkylamino group having an alkyl group having 1 to 6 carbon atoms,
(3) a dialkylamino group having an alkyl group having 1 to 6 carbon atoms, which may be the same or different,
(4) aminomethyl group,
(5) an alkylaminomethyl group having an alkyl group having 1 to 6 carbon atoms, or
(6) a dialkylaminomethyl group having 1 to 6 carbon atoms which may be the same or different,
Represents a group selected from the following [a] to [c] substituted:
[A]: a saturated or partially saturated 4- to 8-membered ring containing one or two heteroatoms which may be selected from a heteroatom of the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom A heterocyclic group of
[B]: a 4-membered to 6-membered cyclic hydrocarbon group which may contain a double bond,
[C]:
The following formula:
-X ¹ - (alkyl group having 1 to 6 carbon atoms)
[Wherein, X ¹ represents an oxygen atom, a sulfur atom, —CH ₂ —, or a formula:
-N (-R ¹¹ )-
(Here, R ¹¹ on the nitrogen atom represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or an aralkyl group having 7 to 9 carbon atoms.)
The structure shown by is shown. ]
Represents a group represented by

Here, the heterocyclic group of [a] and the cyclic hydrocarbon group of [b] may have one or more groups that may be selected from [Substituent group 1] redundantly;
[Substituent group 1]:
Halogen atoms,
Hydroxyl group,
A carboxy group,
An alkyl group having 1 to 6 carbon atoms,
An alkoxy group having 1 to 6 carbon atoms,
An alkylthio group having 1 to 6 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
An alkoxycarbonyl group having 2 to 7 carbon atoms,
6 cycloalkyl groups having 3 carbon atoms,
An aralkyloxy group having 7 to 9 carbon atoms,
An aralkyloxycarbonyl group having 8 to 10 carbon atoms, and the following formula:

^{-C (= O) -N (-R} 12) R 13

(Wherein R ¹² and R ¹³ on the nitrogen atom each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an aryl group having 6 to 10 carbon atoms.)
A group represented by:

R ² is
Hydrogen atom,
A halogen atom,
An alkyl group having 1 to 8 carbon atoms,
An alkenyl group having 2 to 8 carbon atoms,
An alkynyl group having 2 to 8 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms,
A cycloalkenyl group having 5 to 6 carbon atoms,
Monocyclic or bicyclic aryl groups,
A monocyclic or bicyclic heteroaryl group (including 1 to 4 heteroatoms which may be selected in duplicate from a heteroatom of the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom), or

The following formula:
-X ² -R ²¹
[Wherein, X ² represents —C (═O) —, — (CH ₂ ) _n —, —C (═O) —N (—R ²² ) —, or —N (—R ²³ ) —C ( = O)-
n represents any integer of 1 to 3,
R ²¹ is
An alkyl group having 1 to 6 carbon atoms,
A monocyclic or bicyclic aryl group, or a monocyclic or bicyclic heteroaryl group (a heteroatom optionally selected from a heteroatom of the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom) 1 to 4 included.)
Indicate
R ²² and R ²³ each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. ]
Represents a group represented by
These alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group, and heteroaryl group have one or more groups that may be selected from [Substituent Group 2]. May be;

[Substituent group 2]:
A halogen atom,
An amino group,
Hydroxyl group,
A carboxy group,
An alkyl group having 1 to 6 carbon atoms,
An alkoxy group having 1 to 6 carbon atoms,
An alkylthio group having 1 to 6 carbon atoms,
An aryl group having 6 to 10 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
An alkoxycarbonyl group having 2 to 7 carbon atoms,
A 6 cycloalkyl group having 3 carbon atoms and the following formula:

^{-C (= O) -N (-R} 24) R 25

(In the formula, each of R ²⁴ and R ²⁵ on the nitrogen atom independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an aryl group having 6 to 10 carbon atoms.)
A group represented by:

Here, the amino group of [Substituent group 2] is
An alkyl group having 1 to 6 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms,
An aryl group having 6 to 10 carbon atoms,
An aralkyl group having 7 to 12 carbon atoms,
An aromatic heterocyclic group,
The substituent may have one or two groups selected from the group consisting of an alkylsulfonyl group having 1 to 6 carbon atoms and an arylsulfonyl group having 6 to 10 carbon atoms. In the case where there are two, they may combine with each other to form a cyclic structure;

R ³ is
Hydrogen atom,
A linear or branched alkyl group having 1 to 4 carbon atoms,
A cyclic alkyl group having 3 or 4 carbon atoms,
An alkoxy group having 1 to 4 carbon atoms,
A dialkylamino group having the same or different alkyl chain and a total carbon number of 2 to 4,
A group selected from the group consisting of a trihalogenoalkyl group and an alkoxymethyl group having an alkoxy group having 1 to 3 carbon atoms;

R ⁴ is
Cyano group, following formula:
-COOR ⁴¹ or the following formula:
^{-C (= O) -N (-R} 42) R 43
(In these formulas, R ⁴¹ , R ⁴² and R ⁴³ each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.)
Or R ⁴ and R ³ are integrated to form the following formula (showing —R ⁴ —R ³ —):
^{- (C = Y 2) -Y} 1 - (CH 2) p -
(Wherein Y ¹ represents an oxygen atom, a sulfur atom, N—R ⁴⁴ , or C (—R ⁴⁵ ) R ⁴⁶ , Y ² represents an N—R ⁴⁷ , oxygen atom, or sulfur atom; ⁴⁴ , R ⁴⁵ , R ⁴⁶ , and R ⁴⁷ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and p is an integer 1 or 2.)
May form the structure shown by;
formula:

The structural part containing A in the structure represented by represents a 6-membered aromatic ring optionally having 1, 2 or 3 nitrogen atoms;

R ⁵ represents a hydrogen atom or a group selected from the group of substituents represented by the following [i] to [iv]:
[I]:
A halogen atom,
Hydroxyl group,
A carboxy group,
A linear or branched alkyl group having 1 to 6 carbon atoms,
An alkoxy group having 1 to 6 carbon atoms,
An alkoxycarbonyl group having 2 to 7 carbon atoms and a 6 cycloalkyl group having 3 carbon atoms;
[Ii]:
An amino group,
An alkylamino group having an alkyl group having 1 to 6 carbon atoms,
A dialkylamino group having an alkyl group having 1 to 6 carbon atoms, which may be the same or different, and a 4- to 6-membered saturated nitrogen-containing heterocyclic group having a nitrogen atom as a binding site;
[Iii]:
The following formula:

-C (= O) R ⁵¹

(Wherein R ⁵¹ on the carbon atom is
An alkylamino group having an alkyl group having 1 to 6 carbon atoms,
A dialkylamino group having a C 1-6 alkyl group which may be the same or different,
An alkoxy group having 1 to 6 carbon atoms,
An alkyl (alkoxy) amino group having an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms,
Contains one or two heteroatoms which may be selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and contains a 5-membered or 6-membered saturated cyclic ring bonded to the carbonyl on the nitrogen atom. A nitrogen heterocyclic group,
A 5-membered or 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms which may be selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom,
A dialkylamino group having an alkyl group having 1 to 6 carbon atoms, which may be the same, and 1 to 4 heteroatoms which may be selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom An aromatic heterocyclic substituted alkyl group consisting of a 5-membered or 6-membered aromatic heterocyclic group and an alkylene group having 1 to 3 carbon atoms;
A group selected from the group consisting of )
A group represented by:
[Iv]:
The following formula:

^{-N (-R 52) -C (=} O) R 53

(In the formula, R ⁵² and R ⁵³ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.)
A group represented by:
Furthermore, the alkyl part in the group of substituent groups [i] to [iv] and the alkyl part of the alkoxy group may have one or more groups which may be selected from [Substituent group 5]. In addition, the aromatic or saturated heterocyclic group and the nitrogen-containing heterocyclic group are groups formed by adding an alkyl group having 1 to 6 carbon atoms as a linker to [Substituent group 5]. May have one or more groups that may be selected;

[Substituent group 5]:
A halogen atom,
An amino group,
Hydroxyl group,
A carboxy group,
An alkoxy group having 1 to 6 carbon atoms,
An alkylthio group having 1 to 6 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
An alkoxycarbonyl group having 2 to 7 carbon atoms,
6 cycloalkyl groups having 3 carbon atoms,
An aralkyloxy group having 7 to 9 carbon atoms,
An aralkyloxycarbonyl group having 8 to 10 carbon atoms, and the following formula:

^{-C (= O) -N (-R} 54) R 55

(In the formula, each of R ⁵⁴ and R ⁵⁵ on the nitrogen atom independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an aryl group having 6 to 10 carbon atoms.)
A group represented by:

Here, the amino group of [Substituent group 5] is
An alkyl group having 1 to 6 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms,
An aryl group having 6 to 10 carbon atoms,
An aralkyl group having 7 to 12 carbon atoms,
An aromatic heterocyclic group,
A group selected from the group consisting of an alkylsulfonyl group having 1 to 6 carbon atoms and an arylsulfonyl group having 6 to 10 carbon atoms, which may have one or two substituents, and further the amino group When there are two substituents, they may be bonded to each other to form a cyclic structure;
X represents an oxygen atom, a sulfur atom, N—R ⁶ , or —C (—R ⁷¹ ) R ⁷² ;
R ⁶ , R ⁷¹ and R ⁷² each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. ]

2. The above 1. in which X is an oxygen atom. Or 2. Or a salt thereof, or a hydrate thereof.
3. Above 1. Or 2. Or a salt thereof or a hydrate thereof.
4). Above 1. Or 2. An infectious disease therapeutic agent comprising the compound described in 1., a salt thereof, or a hydrate thereof.
5). Above 1. Or 2. Or an antifungal agent comprising the compound or salt thereof, or a hydrate thereof.
6). Above 1. Or 2. A method for treating an infectious disease using the compound, its salt, or a hydrate thereof described in 1. above.
7). Above 1. Or 2. Or a salt thereof, or a hydrate thereof for use in the treatment of infectious diseases.
8). Above 1. Or 2. Use of the compound according to claim 1, a salt thereof, or a hydrate thereof for the manufacture of an infection treatment.

  The present invention provides a compound that can exhibit an antifungal action based on the action mechanism of 1,6-β-glucan synthesis inhibition in a broad spectrum and specifically or selectively, and such a compound, salt thereof Or a pharmaceutical containing the solvate, particularly an infectious disease therapeutic agent or an antifungal agent.

Definitions of terms used in the present specification are as follows. Among these, it may be selected from these according to the limitation of each of the substituents including the symbols R, X, and Y.
The alkyl moiety in the “alkyl group” or a substituent containing an alkyl moiety (for example, an alkoxy group, etc.) may be either linear or branched. Specifically, as an alkyl group, methyl group, ethyl group, normal propyl group, normal butyl group, normal pentyl group, normal hexyl group, normal heptyl group, normal octyl group, normal nonyl group, normal undecyl group, normal dodecyl group Group, normal tridecyl group, normal tetradecyl group, normal pentadecyl group, normal hexadecyl group, normal heptadecyl group, normal octadecyl group, isopropyl group, isobutyl group, secondary butyl group, tertiary butyl group, isopentyl Group, neopentyl group, tertiary pentyl group, isohexyl group, 1,1-dimethylpropyl group, n-heptyl group, n-octyl group and the like.

  “Cycloalkyl group” refers to a monocyclic or bicyclic cyclic alkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or a bicyclo [3.2.1] oct-2-yl group. Etc.

The “alkenyl group” may be linear or branched and has one or more carbon-carbon double bonds. Specifically, vinyl group, propenyl group, buten-1-yl group, isobutenyl group, penten-1-yl group, 2-methylbuten-1-yl group, 3-methylbuten-1-yl group, hexene-1- Yl group, hepten-1-yl group, octen-1-yl group, and the like.
“Cycloalkenyl group” refers to a monocyclic or bicyclic alkenyl group such as 2-cyclopenten-1-yl group, 2,4-cyclopentadien-1-yl group, 5-norbornene-2- Yl group and the like.
The “alkynyl group” may be linear or branched and has one or more carbon-carbon triple bonds. Specific examples include an ethynyl group and a propynyl group.

“Halogen atom” refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
The “aryl group” refers to a monovalent group obtained by removing one hydrogen atom from an aromatic ring of an aromatic hydrocarbon. The aromatic ring constituting the aryl group may be either a single ring or a condensed ring. For example, a phenyl group, a naphthyl group, an anthryl group, an azulenyl group, etc. can be mentioned.
The “aralkyl group” refers to a group in which one or more hydrogen atoms of an alkyl group are substituted with the aryl group. For example, benzyl group, benzhydryl group, trityl group and the like can be mentioned.

  The “heterocyclic group” refers to a group derived from a saturated, partially saturated, or unsaturated heterocyclic compound, and may be monocyclic, bicyclic, or spirocyclic. Examples of the heterocyclic compound that gives a heterocyclic group include aziridine, azetidine, pyrrole, furan, thiophene, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, imidazole, pyrazole, imidazolidine, pyrazolidine, oxazole, isoxazole, thiazole, isothiazole, pyridine. , Dihydropyridine, tetrahydropyran, piperidine, pyridazine, pyrimidine, triazine, pyrazine, pyrrolidone, dioxane, pyran, morpholine, benzofuran, indolizine, benzothiophene, indole, naphthyridine, quinoxaline, quinazoline, chroman, etc. Furthermore, what is represented by the following formula can be illustrated.

Wherein R ⁸¹ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogenoalkyl group having 1 to 6 carbon atoms, or a cycloalkyl group having 3 to 6 carbon atoms, and the substituent Q has the following formula :

-(C (-R ⁹¹ ) R ⁹² ) qN (-R ⁹³ ) R ⁹⁴

B represents an integer of 0, 1, or 2, q represents an integer of 0, 1 or 2, and R ⁹³ and R ⁹⁴ each independently represents a hydrogen atom, a carbon number 1 represents an alkyl group having 1 to 6 or a halogenoalkyl group having 1 to 6 carbon atoms, or represents an amino acid, a dipeptide, or a polypeptide consisting of 3 to 5 amino acids, wherein R ⁹¹ and R ⁹² are each independently , Hydrogen atom, alkyl group having 1 to 6 carbon atoms, halogenoalkyl group having 1 to 6 carbon atoms, hydroxyalkyl group having 1 to 6 carbon atoms, aminoalkyl group having 1 to 6 carbon atoms, alkoxy having 2 to 12 carbon atoms An alkyl group, a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group which may have a substituent, or a heteroaryl group having 3 to 10 carbon atoms which may have a substituent is shown. )

R ⁸¹ is preferably a hydrogen atom or an alkyl group, and the alkyl group is preferably a methyl group, an ethyl group, a normal propyl group, or an isopropyl group.
R ⁹³ and R ⁹⁴ are preferably a hydrogen atom or an alkyl group, and the alkyl group is preferably a methyl group, an ethyl group, a normal propyl group, or an isopropyl group.
R ⁹¹ and R ⁹² are each independently preferably a hydrogen atom, an alkyl group, a halogenoalkyl group, an alkoxylalkyl group, a cycloalkyl group, or a phenyl group. Among these, a hydrogen atom, a methyl group, an ethyl group, a fluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a methoxymethyl group, a cyclopropyl group, a cyclobutyl group, or a phenyl group is more preferable.
R ⁹¹ and R ⁹² may be integrated to form a ring structure having 3 to 6 carbon atoms. Further, this ring may contain a nitrogen atom as an atom constituting the ring. Preferred ring structures include cyclopropyl, cyclobutyl, or cyclopentyl.

The “heteroaryl group” specifically indicates those having aromaticity (or aromaticity) among the above heterocyclic groups, and indicates what is referred to as “aromatic heterocycle”.
For example, a 5-membered or 6-membered monocyclic ring, a bicyclic benzo-fused ring system or a hetero-heterocyclic ring system, a 5-6 condensed ring system, or a 6-6 condensed ring system The thing etc. can be mentioned. For example, pyrrolyl group, furyl group, thienyl group, imidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, tetrazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, triazinyl group, pyrazinyl group, benzofuryl group, An indolyl group, a naphthyridinyl group, a quinoxalinyl group, a quinazolinyl group, and the like can be given.

  Further, in the present specification, the “aromatic heterocyclic group” is a monocyclic 5-membered ring or 6-membered ring among the above heteroaryl groups, and a group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. In particular, those containing 1 to 4 heteroatoms selected from the group consisting of For example, pyrrolyl group, furyl group, thienyl group, imidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, triazinyl group, pyrazinyl group and the like can be mentioned.

  In the present specification, regarding the amino group, hydroxyl group, mercapto group, etc., the “protecting group” in the case of “may be protected by a protecting group” is not particularly limited as long as it is widely used in this field. Are, for example, alkoxycarbonyl groups such as tertiary butoxycarbonyl group and 2,2,2-trichloroethoxycarbonyl group; aralkyloxy such as benzyloxycarbonyl group, paramethoxybenzyloxycarbonyl group and paranitrobenzyloxycarbonyl group Carbonyl groups; acyl groups such as acetyl group, methoxyacetyl group, trifluoroacetyl group, chloroacetyl group, pivaloyl group, formyl group, benzoyl group; tertiary butyl group, benzyl group, paranitrobenzyl group, paramethoxy Alkyl groups such as benzyl group and triphenylmethyl group; Are aralkyl groups; ethers such as methoxymethyl group, tertiary butoxymethyl group, tetohydropyranyl group, 2,2,2-trichloroethoxymethyl group; trimethylsilyl group, isopropyldimethylsilyl group, tertiary butyldimethyl group Mention may be made of (alkyl and / or aralkyl) substituted silyl groups such as silyl groups, tribenzylsilyl groups, tertiary butyldiphenylsilyl groups. Further, the amino group may be protected as phthalimide.

  “Amino acid, dipeptide, or group derived from a polypeptide consisting of 3 to 5 amino acids” or “amino acid, dipeptide, or polypeptide consisting of 3 to 5 amino acids bound to an amino group” For example, amino acids, dipeptides, and tripeptides, or substituted carbonyl groups derived therefrom. That is, amino acids such as glycine, alanine, aspartic acid, dipeptides such as glycine-glycine, glycine-alanine, alanine-alanine, and tripeptides such as glycine-glycine-alanine, glycine-alanine-alanine, or from these Mention may be made of substituted carbonyl groups which are derived.

The partial structure and substituent of the compound represented by the formula (I) of the present invention will be described.
Formula (I):

The compound represented in the substituents R ¹ from R ^3, and R ^5, and the tricyclic nucleus (R ³ and R ⁴ cyclic structure by integrating the cyano group as a substituent R ⁴ which mainly When formed, it becomes a tetracyclic mother nucleus). In addition, as for this tricyclic mother nucleus, both the ring containing X and the cyclic part containing A are aromatic rings, and it has a tricyclic aromatic cyclic structure as a whole. These substituents will be described below.

R ¹ is a basic group. The basic group includes a saturated or partially saturated 4-membered to 8-membered nitrogen-containing heterocyclic group containing 1 or 2 nitrogen atoms, and a base having a basic substituent described below. May be a sex group.

  In the case of the former nitrogen-containing heterocyclic group, the nitrogen atom part in a ring functions as a basic expression part. Therefore, when there is one nitrogen atom, the nitrogen atom does not serve as a binding site to the tricyclic mother nucleus. In addition, an alkyl group having 1 to 6 carbon atoms may be substituted on the nitrogen atom. The nitrogen-containing heterocyclic group may have a size of 4 to 8 members, but preferably has a size of 4 to 6 members. This ring may be a saturated ring or may be partially saturated including a double bond. When the nitrogen-containing heterocyclic group contains a double bond, those in a position conjugated with the tricyclic mother nucleus are preferred.

The latter basic group having a basic substituent is a group shown below. First of all basic substituents;
(1) an amino group,
(2) an alkylamino group having an alkyl group having 1 to 6 carbon atoms,
(3) a dialkylamino group having an alkyl group having 1 to 6 carbon atoms, which may be the same or different,
(4) aminomethyl group,
(5) an alkylaminomethyl group having an alkyl group having 1 to 6 carbon atoms, or
(6) a dialkylaminomethyl group having an alkyl group having 1 to 6 carbon atoms, which may be the same or different,
If it is.
Examples of (2) are methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, sec-butylamino group and the like. The alkyl group may be linear or branched.
As an example of (3), the nitrogen atom of the alkylamino group shown in the above (2) is further alkylated by an alkyl group having 1 to 6 carbon atoms. Methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group and the like. Two alkyl groups may be the same or different.
(4), (5), or (6) aminomethyl group or alkylaminomethyl group, dialkylaminomethyl group is the amino group of the above (1) or the alkylamino described in (2) or (3) It may be composed of a group or a dialkylamino group and a methylene group (—CH ₂ —).

The basic substituent is preferably an alkylamino group or a dialkylamino group, and specifically, a methylamino group, an ethylamino group, or a dimethylamino group is preferable.
The basic substituents (1) to (6) above are substituted on the groups shown as the following [a] to [c] to form a basic group.
[A]: a saturated or partially saturated 4- to 8-membered heterocycle containing heteroatoms 1 or 2 which may be selected from a heteroatom of the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom A ring group,
[B]: a 4-membered to 6-membered cyclic hydrocarbon group which may contain a double bond,
[C]:
The following formula:
-X ¹ - (alkyl group having 1 to 6 carbon atoms)
[Wherein, X ¹ represents an oxygen atom, a sulfur atom, —CH ₂ —, or a formula:
-N (-R ¹¹ )-
(Here, R ¹¹ on the nitrogen atom represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or an aralkyl group having 7 to 9 carbon atoms.)
The structure shown by is shown. ]
The group shown by is shown.

Here, the heterocyclic group of [a] and the cyclic hydrocarbon group of [b] may have one or more groups which may be selected from [Substituent group 1] redundantly;
[Substituent group 1]:
A halogen atom,
Hydroxyl group,
A carboxy group,
An alkyl group having 1 to 6 carbon atoms,
An alkoxy group having 1 to 6 carbon atoms,
An alkylthio group having 1 to 6 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
An alkoxycarbonyl group having 2 to 7 carbon atoms,
6 cycloalkyl groups having 3 carbon atoms,
An aralkyloxy group having 7 to 9 carbon atoms,
An aralkyloxycarbonyl group having 8 to 10 carbon atoms, and the following formula:
^{-C (= O) -N (-R} 12) R 13
(Wherein R ¹² and R ¹³ on the nitrogen atom each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an aryl group having 6 to 10 carbon atoms.)
A group represented by

As the saturated or partially saturated heterocyclic group shown in [a], a heterocyclic group satisfying the following requirements may be selected from the heterocyclic groups shown above.
1. The hetero atom contained is one or two that may be selected from a hetero atom of the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom,
2. 2. saturated or partially saturated; It is monocyclic and is a 4, 5 or 6 membered ring.
For example, an azetidinyl group, a pyrrolidinyl group, or a piperidinyl group can be exemplified as a heterocyclic group, and further, a heterocyclic group having a sulfur atom or an oxygen atom as a second hetero atom can be exemplified as these pyrrolidinyl group and piperidinyl group. Can do.
Of these, a saturated 5-membered heterocyclic group having a nitrogen atom as a hetero atom is more preferred. Further, this heterocyclic group is preferably bonded to the tricyclic mother nucleus at the nitrogen atom.

  Preferred examples of the cyclic hydrocarbon group shown in [b] include a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group, and a cyclobutenyl group, a cyclopentenyl group, and a cyclohexenyl group containing a double bond. . In the hydrocarbon group having a double bond, the position of the double bond is a position where the carbon atom bonded to the tricyclic mother nucleus becomes one carbon atom of the double bond and is conjugated with the tricyclic mother nucleus. It is preferable.

  In the groups [a] and [b], the group [a] or [b] having a basic substituent is a 5-membered saturated heterocyclic group having an aminomethyl group or a dialkylamino group. Or a hydrocarbon group having one double bond. Among these, a 5-membered saturated heterocyclic group having a dialkylamino group or a hydrocarbon group having one double bond is preferable. More specifically, a 1-pyrrolidinyl group, a cyclopentyl group, or a 1-cyclopentenyl group having a methylamino group or a dimethylamino group is preferable.

  The carbon atom to which the basic substituent is bonded may further have a substituent. As such a substituent, an alkyl group having 1 to 6 carbon atoms is preferable, a methyl group or an ethyl group is preferable, and a methyl group is more preferable. These are shown below.

The group represented by [c] is an alkyl group containing a nitrogen atom, oxygen atom, methylene, or sulfur atom as a linker with a tricyclic mother nucleus. The alkyl moiety has 1 to 6 carbon atoms and may be linear or branched. The position of the basic substituent on the alkyl may be any, but those at the end of the alkyl chain are more preferable.
The linker is preferably a nitrogen atom, and more preferably an alkyl group as a substituent on the nitrogen atom. The chain length including the linker moiety is preferably a chain length of 3 or 4 atoms.

As the basic group for R ¹ , those having a cyclic structure are more preferred. That is, a structure having a basic substituent on the substituent represented by [a] or [b] is preferable.

R ² is
Hydrogen atom,
A halogen atom,
An alkyl group having 1 to 8 carbon atoms,
An alkenyl group having 2 to 8 carbon atoms,
An alkynyl group having 2 to 8 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms,
A cycloalkenyl group having 5 to 6 carbon atoms,
Monocyclic or bicyclic aryl groups,
A monocyclic or bicyclic heteroaryl group (containing 1 to 4 heteroatoms which may be selected from a heteroatom of the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom), or :
-X ² -R ²¹
[Wherein, X ² represents —C (═O) —, — (CH ₂ ) _n —, —C (═O) —N (—R ²² ) —, or —N (—R ²³ ) —C ( = O)-
n represents any integer of 1 to 3,

R ²¹ is
An alkyl group having 1 to 6 carbon atoms,
A monocyclic or bicyclic aryl group, or a monocyclic or bicyclic heteroaryl group (a heteroatom optionally selected from a heteroatom of the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom) 1 to 4 included.)
R ²² and R ²³ each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. ].

In these groups, the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the cycloalkenyl group, the aryl group, and the heteroaryl group are one group that may be selected from [Substituent Group 2]. You may have more.
[Substituent group 2]:
A halogen atom,
An amino group,
Hydroxyl group,
A carboxy group,
An alkyl group having 1 to 6 carbon atoms,
An alkoxy group having 1 to 6 carbon atoms,
An alkylthio group having 1 to 6 carbon atoms,
An aryl group having 6 to 10 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
An alkoxycarbonyl group having 2 to 7 carbon atoms,
A 6 cycloalkyl group having 3 carbon atoms and the following formula:
^{-C (= O) -N (-R} 24) R 25
(In the formula, each of R ²⁴ and R ²⁵ on the nitrogen atom independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an aryl group having 6 to 10 carbon atoms.)
It is group shown by these.

Furthermore, the amino group of [Substituent group 2] is
An alkyl group having 1 to 6 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms,
An aryl group having 6 to 10 carbon atoms,
An aralkyl group having 7 to 12 carbon atoms,
An aromatic heterocyclic group,
One or two groups selected from the group consisting of an alkylsulfonyl group having 1 to 6 carbon atoms and an arylsulfonyl group having 6 to 10 carbon atoms may be used as a substituent. When there are two, they may be bonded to each other to form a cyclic structure.

As R ² ,
A monocyclic or bicyclic aryl group, or a monocyclic or bicyclic heteroaryl group (from one heteroatom which may be selected in duplicate from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom) 4 is included).
As the aryl group, a monocyclic group is preferable, and a phenyl group is preferable. This phenyl group may have a substituent, and a hydroxyl group, an amino group, or the like may be substituted. As the aryl group, a 2-hydroxyphenyl group, a 2-aminophenyl group, and the like are preferable.
The heteroaryl group is preferably a monocyclic 5- or 6-membered heteroaryl group. The 5- or 6-membered heteroaryl group includes a hetero atom or 2 that may be selected from a nitrogen atom, an oxygen atom, and a sulfur atom as a hetero atom. Examples thereof include a furyl group, a thiazolyl group, a pyridyl group, a pyrimidyl group, and a pyridazyl group.
Among these, 4-thiazolyl group, 2-furyl group, 2-pyrrolyl group, 3-pyridyl group, 2-pyridyl group and the like are preferable. Of these, 4-thiazolyl group and 2-furyl group are preferable. The heteroary group may have a substituent, and an alkyl group having 1 to 6 carbon atoms may be substituted. The alkyl group is preferably a methyl group. As the heteroaryl group, a 2-methyl-4-thiazolyl group and a 2-furyl group are preferable.
In addition to the aryl group and heteroaryl group, a halogen atom is preferable, and a chlorine atom or a bromine atom is preferable.

R ³ is
Hydrogen atom,
A linear or branched alkyl group having 1 to 4 carbon atoms,
A cyclic alkyl group having 3 or 4 carbon atoms,
An alkoxy group having 1 to 4 carbon atoms,
A dialkylamino group having the same or different alkyl chain and a total carbon number of 2 to 4,
An alkoxymethyl group having a trihalogenoalkyl group and an alkoxy group having 1 to 3 carbon atoms,
A group selected from the group consisting of
R ³ is preferably a bulky group having about 1 to 4 carbon atoms. For example, methyl group, ethyl group, isopropyl group, cyclopropyl group, cyclobutyl group, dimethylamino group, ethylmethylamino group, diethylamino group, trifluoromethyl group, methoxymethyl group, ethoxymethyl group, methoxyethyl group and the like.
R ³ is preferably a methyl group or an ethyl group.

R ⁴ is
Cyano group, following formula:
-COOR ⁴¹ or the following formula:
^{-C (= O) -N (-R} 42) R 43
(In these formulas, R ⁴¹ , R ⁴² and R ⁴³ each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.)
Or R ⁴ and R ³ are integrated to form the following formula (showing —R ⁴ —R ³ —):
^{- (C = Y 2) -Y} 1 - (CH 2) p -
(Wherein Y ¹ represents an oxygen atom, a sulfur atom, N—R ⁴⁴ , or C (—R ⁴⁵ ) R ⁴⁶ , Y ² represents an N—R ⁴⁷ , oxygen atom, or sulfur atom; ⁴⁴ , R ⁴⁵ , R ⁴⁶ , and R ⁴⁷ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and p is an integer 1 or 2.)
You may form the structure shown by these.

When R ⁴ does not form a cyclic structure, is this a cyano group or —COOR ⁴¹
Or a carboxy group or an ester group represented by
^{-C (= O) -N (-R} 42) R 43
And a carboxamide group which may have 1 or 2 substituents on the nitrogen atom.
When R ⁴ is an ester group, an alkyl ester having an alkyl group having 1 to 6 carbon atoms is preferable, and examples thereof include a methyl ester, an ethyl ester, a propyl ester, and a butyl ester.
In addition, when R ⁴ is carboxamide, it may have an alkyl group 1 or 2 having 1 to 6 carbon atoms on the nitrogen atom, and carboxamide, methyl carboxamide, ethyl carboxamide, propyl carboxamide, N, N- Examples thereof include dimethylcarboxamide, N-methyl-N-ethylcarboxamide, N, N-diethylcarboxamide and the like.

The structure formed when R ⁴ is integrated with R ³ includes a part of the mother nucleus to form a cyclic structure, and the ring thus formed is a 5-membered ring (p = 1) or 6 The size of the member ring (p = 2). The ring size is preferably a 5-membered ring. In addition,
^{- (C = Y 2) -Y} 1 - (CH 2) p -
The structure shown as indicates that they are integrated as -R ⁴ -R ^3- , that is, the left end bond is derived from R ⁴ and the right end bond is derived from R ³ . . An example of a specific structure including the structure integrated in this way is shown below.

Y ¹ represents an oxygen atom, a sulfur atom, N—R ⁴⁴ , or C (—R ⁴⁵ ) R ^46, and among these, an oxygen atom, N—R ⁴⁴ , or C—R ⁴⁵ is preferable. More preferably an oxygen atom or N—R ⁴⁴ .
When Y ¹ is N—R ⁴⁴ , R ⁴⁴ is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. Examples of the alkyl group having 1 to 6 carbon atoms include methyl group, ethyl group, propyl group, butyl group Examples include groups. R ⁴⁴ is preferably a hydrogen atom, a methyl group, or an ethyl group.
When Y ¹ is C (—R ⁴⁵ ) R ⁴⁶ , R ⁴⁵ and R ⁴⁶ are a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and these may be considered in the same manner as R ^44, and R ⁴⁵ and R ^{46 As 46} , all are hydrogen atoms, or one is a hydrogen atom, the other is an alkyl group having 1 to 6 carbon atoms, and all are combinations of alkyl groups having 1 to 6 carbon atoms. R ⁴⁵ and R ⁴⁶ are preferably hydrogen atoms, hydrogen atoms and methyl groups, or a combination of both methyl groups.
Y ² represents an oxygen atom, a sulfur atom or ═NR ^47, and among these, an oxygen atom is preferable.
formula:

The structural part containing A represents a 6-membered aromatic ring which may have one or two nitrogen atoms.
That is, the compound of the present invention is a tricyclic compound, and further becomes a tetracyclic compound when R ⁴ is integrated with R ³ .
The ring structure of this part is either a hydrocarbon ring or a nitrogen-containing aromatic heterocycle in which 1 to 3 of the carbon atoms are nitrogen atoms. The size of the ring is a six-membered ring, which is an aromatic ring. When the structural part containing A is a hydrocarbon ring, the structure in the case of a further aromatic ring containing a nitrogen atom 1 is shown below.

R ⁵ represents a hydrogen atom or a group selected from the substituent group represented by the following [i] to [iv];
[I]:
A halogen atom,
Hydroxyl group,
A carboxy group,
A linear or branched alkyl group having 1 to 6 carbon atoms,
An alkoxy group having 1 to 6 carbon atoms,
An alkoxycarbonyl group having 2 to 7 carbon atoms and a 6 cycloalkyl group having 3 carbon atoms;
[Ii]:
An amino group,
An alkylamino group having an alkyl group having 1 to 6 carbon atoms,
A dialkylamino group having a C 1-6 alkyl group which may be the same or different,
A 4- to 6-membered saturated nitrogen-containing heterocyclic group having a nitrogen atom as a binding site, and a 4- to 6-membered saturated nitrogen-containing heterocyclic group having a carbon atom as a binding site;
[Iii]:
The following formula:
-C (= O) R ⁵¹
(Wherein R ⁵¹ on the carbon atom is
An alkylamino group having an alkyl group having 1 to 6 carbon atoms,
A dialkylamino group having a C 1-6 alkyl group which may be the same or different,
An alkoxy group having 1 to 6 carbon atoms,
An alkyl (alkoxy) amino group having an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms,
A 5- or 6-membered saturated cyclic nitrogen-containing complex containing a heteroatom 1 or 2 which may be selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and bonded to carbonyl on the nitrogen atom A ring group,
A 5-membered or 6-membered aromatic heterocyclic group containing a hetero atom 1 to 4 which may be selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom,
1 to 4 heteroatoms which may be selected from the group consisting of a dialkylamino group having 1 to 6 carbon atoms, which may be the same, and a nitrogen atom, an oxygen atom and a sulfur atom. An aromatic heterocyclic substituted alkyl group comprising a 5-membered or 6-membered aromatic heterocyclic group and an alkylene group having 1 to 3 carbon atoms,
A group selected from the group consisting of )
A group represented by:
[Iv]:
The following formula:
^{-N (-R 52) -C (=} O) R 53
(In the formula, R ⁵² and R ⁵³ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.)
A group represented by:
Furthermore, the alkyl part in the group of substituent groups [i] to [iv] and the alkyl part of the alkoxy group may have one or more groups that may be selected from [Substituent group 5]. In addition, the aromatic or saturated heterocyclic group and the nitrogen-containing heterocyclic group are groups formed by adding an alkyl group having 1 to 6 carbon atoms as a linker to [Substituent group 5], and overlapping each other. May have one or more groups that may be selected.

[Substituent group 5]:
A halogen atom,
An amino group,
Hydroxyl group,
A carboxy group,
An alkoxy group having 1 to 6 carbon atoms,
An alkylthio group having 1 to 6 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
An alkoxycarbonyl group having 2 to 7 carbon atoms,
6 cycloalkyl groups having 3 carbon atoms,
An aralkyloxy group having 7 to 9 carbon atoms,
An aralkyloxycarbonyl group having 8 to 10 carbon atoms, and the following formula:
^{-C (= O) -N (-R} 54) R 55
(In the formula, each of R ⁵⁴ and R ⁵⁵ on the nitrogen atom independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an aryl group having 6 to 10 carbon atoms.)
A group represented by

Here, the amino group of [Substituent group 5] is
An alkyl group having 1 to 6 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms,
An aryl group having 6 to 10 carbon atoms,
An aralkyl group having 7 to 12 carbon atoms,
An aromatic heterocyclic group,
A group selected from the group consisting of an alkylsulfonyl group having 1 to 6 carbon atoms and an arylsulfonyl group having 6 to 10 carbon atoms may have as one or two substituents, and the amino group When there are two substituents, each may be bonded to each other to form a cyclic structure.

  Of the groups represented by [i], an alkyl group having a chain length of about 2 or 3 is preferred as the chain alkyl group. For example, an ethyl group, an isopropyl group, and a tertiary butyl group. On the other hand, the cyclic alkyl group is preferably a cyclopropyl group. These may have a substituent, and may be substituted with a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or an aralkyloxy group having 2 to 9 carbon atoms. The alkoxy group is preferably a methoxy group.

The group shown as [ii] is an amine type substituent. These may be either a chain structure or a cyclic structure.
Examples of the chain structure include an alkylamine type and a dialkylamine type, and any of them may be used. A simple amino group from which these alkyl groups have been removed may be used. Examples of the alkyl group on the nitrogen atom include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and a sec-butyl group. The alkyl group may be linear or branched. These alkyl groups may have a substituent, and may have a hydroxyl group, a carboxy group, a (substituted) carboamido group, or the like. Among these, an amino group, a methylamino group, a dimethylamino group, a diethylamino group, a methylethylamino group, a methylisopropylamino group, and a methyl tertiary butylamino group are preferable. Those having a hydroxyl group include a 2-hydroxyethylmethylamino group, a 2- (dimethylaminocarbonyl) ethylmethylamino group, and a 3- (dimethylaminocarbonyl) propylmethylamino group.
The cyclic structure is preferably a saturated 4- to 6-membered nitrogen-containing heterocyclic substituent, in which the nitrogen atom is the binding site to the bicyclic mother nucleus. An azetidinyl group, a pyrrolidinyl group, a piperazinyl group, and the like. These may have a substituent as well as a chain structure, and may have a hydroxyl group or a carboxy group. Examples thereof include a 3-hydroxyazetidinyl group and a 3-carboxyazetidinyl group.

What is shown in [iii] is a substituent having a carbonyl group as a binding site, and is a substituent having an ester or amide structure.
In the case of an ester structure, the group bonded to the carbonyl group may be an alkoxy group having 1 to 6 carbon atoms, and this alkyl moiety may be either linear or branched. Examples of such an alkoxy group include a methoxy group, an ethoxy group, a propoxy group, and an isopropoxy group. The alkoxy group in this part is preferably an ethoxy group.

As a substituent which becomes an amide structure, a substituted amino group may be bonded to a carbonyl group, and this substituted amino group may be a chain structure or a cyclic structure. The cyclic structure includes a nitrogen atom bonded to the carbonyl group and forms a cyclic structure. For example, the alkyl group forming the alkylamino group has 1 to 6 carbon atoms and may be linear or branched. For example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group and the like. Examples of such alkylamino groups include a methylamino group, a dimethylamino group, a diethylamino group, and a methylethylamino group. This alkyl group may further have a substituent, and may have a hydroxyl group, an alkoxy group, a (substituted) aminocarbonyl group, or the like. For example, 2-hydroxyethylmethylamino group, 2-methoxyethylmethylamino group, (dimethylaminocarbonylmethyl) methylamino group, and the like.
Further, an alkoxyalkylamino group in which an alkoxy group is further substituted on the nitrogen atom may be used. For example, a methylmethoxyamino group can be mentioned.

  In the case of an amino group having a cyclic structure, it is a 5- or 6-membered saturated nitrogen-containing heterocyclic substituent, and the nitrogen atom serves as a carbonyl group binding site. Specifically, it is a pyrrolidinyl group or a piperazinyl group, but the ring may further contain one or more hetero atoms of a nitrogen atom, an oxygen atom or a sulfur atom. When the second hetero atom is a nitrogen atom, it may have a substituent and may have an alkyl group having 1 to 6 carbon atoms, an acyl group having 2 to 7 carbon atoms, or the like. Examples of such a cyclic alkyl group include a piperazinyl group, a morpholinyl group, and a piperidinyl group. Examples of those having a substituent include a 4-acetylpiperazinyl group.

  The group shown as [iv] is a substituted amide group having a nitrogen atom as a binding site. The substituent on the carbonyl group and the nitrogen atom may be a hydrogen atom or an alkyl group, but both are preferably alkyl groups. Particularly preferred is a case where both are methyl groups.

X represents an oxygen atom, a sulfur atom, N—R ⁶ , or C (—R ⁷¹ ) R ⁷² , wherein R ⁶ , R ⁷¹ and R ⁷² are each independently a hydrogen atom or a carbon number of 1 to 6 Represents an alkyl group.
R ⁶ , R ⁷¹ and R ⁷² are a hydrogen atom or an alkyl group, but in the case of an alkyl group, a methyl group is preferred. X is preferably an oxygen atom.

  When the compound represented by the formula (I) of the present invention has a structure in which an enantiomer (enantiomer) exists, each enantiomer, a racemate that is a mixture of the 1: 1 ratio, and each enantiomer are appropriately mixed. Any enantiomeric mixture present in ratio and having an optical purity of less than 100% is encompassed by the compounds of the invention. Furthermore, when the compound represented by the formula (I) has a structure in which a diastereomer exists, the compound of the present invention includes a single diastereomer and a mixture of diastereomers.

  When the compound represented by the formula (I) has a structure in which an enantiomer is present, it is desirable to administer a compound consisting of a single enantiomer when the compound of the present invention is administered to humans or animals. The term “consisting of a single enantiomer” is understood to include not only the case where the other enantiomer (enantiomer) is not contained at all, but also the case where it can be usually said that it is chemically pure. That is, it is understood that the other enantiomer (enantiomer) may be included as long as it does not affect the physical constant and physiological activity.

  Furthermore, when the compound represented by formula (I) has a structure in which diastereomers are present, it is desirable to administer a compound consisting of a single diastereomer when the compound of the present invention is administered to humans or animals. . The term “consisting of a single diastereomer” is understood to include not only the case where no other diastereomer is contained, but also a case where it can be usually said that it is chemically pure. That is, it is understood that other diastereomers may be included as long as they do not affect physical constants and physiological activities.

  In addition, “stereochemically single” means that a compound or the like contains an asymmetric carbon atom, and therefore is composed of only one of them when it is in an isomer relation. Indicates. In this case as well, this “single” interpretation is considered in the same manner as above.

When the compound represented by the formula (I) is an acid derivative having a phenolic hydroxyl group, a carboxy group (carboxylic acid derivative), or a sulfo group (sulfonic acid derivative) in an arbitrary substituent moiety, those acid derivatives are It may be a free form, but may be a salt of a phenolic hydroxyl group, a carboxy group, or a sulfo group.
Examples of these salts include alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, ammonium salt, triethylamine salt and N-methylglucamine salt, Any of inorganic salts and organic salts such as tris- (hydroxymethyl) aminomethane salt may be used. In addition, free forms and salts of these acid derivatives may exist as hydrates.

On the other hand, when the compound represented by the formula (I) is a basic derivative having an amino group or an amine structure at an arbitrary substituent moiety, these basic derivatives may remain in a free form, but acid addition salts It is good.
Examples of acid addition salts include hydrochlorides, sulfates, nitrates, hydrobromides, hydroiodides, phosphates and other inorganic acid salts, or methanesulfonates and benzenesulfonates. And organic acid salts such as paratoluenesulfonate (sulfonate), acetate, citrate, maleate, fumarate, lactate, and tartrate (carboxylate). Moreover, the free body and salt of these basic derivatives may exist as a hydrate.

When the compound represented by formula (I) is a carboxylic acid compound, the derivative in which the carboxylic acid moiety is an ester is useful as a synthetic intermediate or prodrug. For example, alkyl esters, benzyl esters, alkoxyalkyl esters, phenylalkyl esters and phenyl esters are useful as synthetic intermediates.
In addition, when the carboxylic acid compound of the present invention is used for antifungal purposes, the ester used as a prodrug is an ester that is easily cleaved in vivo to produce a free carboxylic acid, for example, Acetoxymethyl ester, pivaloyloxymethyl ester, ethoxycarbonyl ester, choline ester, dimethylaminoethyl ester, 5-indanyl ester and phthalidinyl ester, 5-alkyl-2-oxo-1,3-dioxol-4-yl Mention may be made of methyl esters and oxoalkyl esters such as 3-acetoxy-2-oxobutyl ester.

Furthermore, the compound represented by the formula (I) is a basic compound having an amino group, and a derivative in which an amino acid, a dipeptide, or a tripeptide is bonded to the amino group is useful as a prodrug.
As amino acids, dipeptides, and tripeptides used as prodrugs, peptide bonds formed from these carboxy groups and the amino group of formula (I), which is a compound of the present invention, are easily cleaved in vivo to release amines. For example, amino acids such as glycine, alanine, aspartic acid, dipeptides such as glycine-glycine, glycine-alanine, alanine-alanine, and glycine-glycine-alanine, glycine-alanine- Mention may be made of tripeptides such as alanine.

  The compound of the present invention represented by the formula (I) can be produced by various methods. As a preferred example, a typical production method is shown and described in the following formula, but is not limited thereto. In the reaction, the substituent is protected with a protecting group as necessary, and the conversion order of each substituent (functional group) is not particularly limited.

(In the formula, ^Ra is a hydroxyl-protecting group such as ^a lower alkyl group, and X ¹ , X ² , and X ³ each independently represent a halogen atom or OR ^b (for example, OTf, OMs, etc.))

Production Method 1-1 is a method for producing a substituted benzonitrile (9) that can be used as a synthetic intermediate when the compound represented by Formula (I) is produced.
That is, compound (9) can be produced from compound (1) (commercially available: X ¹ = F) through the following steps 1 to 8.

Step 1: halogenated (. Ex Br ₂ - acetic acid)
Step 2: Nitration (ex. Fuming nitric acid-concentrated sulfuric acid)
Step 3: Protection of hydroxyl and carboxyl groups (ex. Methylation with dimethyl sulfate)
Process 4: Reduction of nitro group (ex. Iron powder)
Step 5: Deprotection of carboxyl group (ex. Hydrolysis under alkaline conditions)
Steps 6 and 7: Conversion of carboxyl group to nitrile group Step 8: Halogenation (ex. N-iodosuccinimide-acetic acid)
Production method 1-2:

Wherein X ¹ , X ² , X ³ and X ⁴ represent a halogen atom or OR ^b (for example, OTf, OMs, etc.), and R ¹ , R ² and R ³ are substitutions of (I) (Same as definition of group)

Production Method 1-2 is a method for producing a compound represented by Formula (I) from the benzonitrile compound (10) obtained in Production Method 1-1.
That is, the compound represented by the formula (I) can be produced from the compound (10, exemplification: X ¹ = F, X ² = Br, X ³ = I, R ^b = Me) through the following steps 9 to 14.

Step 9: the presence of a palladium catalyst relative substituents X ³ on the benzene ring, exerts a boronic acid or boronic acid esters (Suzuki coupling) conditions and, to apply a tin compound (Stille coupling) conditions due This is a step of introducing a substituent corresponding to R ³ or a substituent to be a precursor thereof.
Step 10: the presence of a palladium catalyst relative substituents X ² on the benzene ring, exerts a boronic acid or boronic acid esters (Suzuki coupling) condition and, due to the action of the tin compound (Stille coupling) condition This is a step of introducing a substituent corresponding to R ³ or a substituent to be a precursor thereof.
Step 11: a step of converting the amino group to X ⁴ due Sandmeyer reaction.
Step 12: Tetrahedron, 58, 3323 ( 2002) or Tetrahedron, 58, 4369 (2002) boronic acid and boronic acid esters obtained by the method described, the presence of a palladium catalyst relative to the substituent X ⁴ on the benzene ring This is a step of introducing an aryl group according to conditions (Suzuki coupling) to act or conditions (Stille coupling) to act a tin compound.
Step 13: A step of removing a protecting group (R ^b ) of the substituent OR ^b on the benzene ring and forming a furan ring.
Step 14: This is a step for producing a compound of the present invention represented by the formula (I) by allowing an amine derivative to act on the substituent X ¹ on the benzene ring. In this case, when R ¹ is an aryl group, heteroaryl group, cycloalkenyl group, or alkyl group, it can be derived from the product obtained by the above-described Suzuki coupling condition or Stille coupling condition.

  The order of step 9 to step 14 can be appropriately converted depending on the substituent (functional group) to be introduced, the chemical properties of the product, etc., and the introduced substituent can protect the functional group and protect the group as necessary. And functional group conversion can be appropriately performed.

(In the formula, X ⁵ represents a halogen atom or OR ^c (for example, OTf, OMs, etc.), and R ¹ , R ^2, and R ³ have the same definition as the substituent of compound (I).)

Production method 2 is a method for producing a target compound represented by the formula (I) from a compound (16, for example, the lower part represents a ring of -B = C-D = E- by a benzene ring).
That is, the compound represented by the formula (I) of the present invention can be produced from the compound (16, exemplarily: all of B, C, D, and E are CH) through the following steps 15 to 19.

Step 15: In this step, an acetic acid unit is introduced by a Wittig reaction or the like to lead to a benzofuranyl acetic acid (benzofuranyl acetonitrile) derivative (17).
Step 16: A step of reacting an acid chloride in the presence of a Lewis acid catalyst such as TiCl ₄ to obtain an acyl form (17).
Step 17: Step of reacting dimethylacetamide dimethyl acetal to construct a dibenzofuran skeleton (R ³ = Me).
Step 18: Conversion of an ester moiety (COOR ^b ) to a nitrile group and conversion from OR ^c to X ⁵ as necessary.
Step 19: A step of producing a compound of the present invention represented by the formula (I) by allowing an amine derivative to act on the substituent X ⁵ . In this case, when R ¹ is an aryl group, heteroaryl group, cycloalkenyl group, or alkyl group, it can be derived from the product obtained by the above-described Suzuki coupling condition or Stille coupling condition.
The substituent introduced in Step 15 to Step 19 can be appropriately protected with a functional group, removed with a protective group, or converted into a functional group, if necessary.

  The compounds of the present invention exhibit specific antibacterial and antifungal effects without any antibacterial or anticancer activity, and are active against a wide range of fungi that cause various fungal infections. Can treat, prevent or alleviate diseases caused by various pathogens.

  Examples of fungi in which the compounds of the present invention are effective include Candida albicans, Candida glabrata, Candida crusei, Candida tropicalis and other Candida species, Cryptococcus neoformans and other Cryptococcus spp., Aspergillus fumigatus, Aspergillus・ Plascoccidioides such as Aspergius genus such as Flabusus, Pneumocystis carinii, Kumonskabi genus, Absidia genus, Histoplasma genus such as Histoplasma capsultrum, Coccidioides genus such as Coccidioides imitis, Blast Myces genus, Paracoccidioides brasiliensis etc. Genus, Penicillium, Pseudolesia, Sporotrix, Black Fungus, Trichophyton, Microsporum, Epidermophyton, Malassezia, Ho Senkaea genus Fusarium, Paecilomyces spp, Trichosporon such Trichosporon Kutaneumu, Hiarohora genus can be exemplified Cladosporium and the like. Furthermore, Saccharomyces cerevisiae, Candida albicans, Candida glabrata, Candida crusei, Candida tropicalis, Cryptocox neoformans, Trichosporon tantaneum, Aspergillus fumigatus and the like can be exemplified.

  In addition, diseases caused by these pathogens include visceral mycosis (deep mycosis) such as candidiasis, cryptococcosis, aspergillus (filamentous fungi), actinomyces (actinomycosis), nocardiosis, Mucormycosis (zygomycosis), geotrichumosis, histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, blastomysosis, penicillosis, etc. Specifically, mycosis, respiratory mycosis, digestive mycosis, urinary tract Mycosis, fungal meningitis, etc., deep dermatomycosis, sporotricosis, chromomycosis (melanocytic mycosis), mycoma (mysetoma), etc. Examples include deep ringworm, refractory ringworm, onychomycosis, folding screen, cutaneous candidiasis, oral candidiasis and the like.

The administration method, dose, and number of administrations of the medicament of the present invention are not particularly limited, and can be appropriately selected according to various conditions such as the type of pathogenic fungus, the age, weight, and symptoms of the patient. Usually, for an adult, 0.1 to 100 mg / kg may be divided into 1 to several times a day by oral or parenteral (injection, infusion, etc.) administration.
The compounds of the present invention are also effective against various fungi that cause fungal infections in animals.

  Utilizing the antifungal action of the compound of the present invention against pathogenic fungi, it can be used as a medicament containing the compound of the present invention, a salt thereof, or a solvate thereof, a therapeutic agent for infectious diseases, or an antifungal agent. It can also be applied to animal drugs, marine products, or antifungal preservatives.

  You may use the compound of this invention, its salt, or these solvates for the manufacture of the pharmaceutical containing these, an infectious disease therapeutic agent, or an antifungal agent. For example, the compound of the present invention, a salt thereof, or a solvate thereof may be used for the production of an injection or solution provided in a solution state. In addition, a pharmaceutical, an infectious disease treatment agent, or an antifungal agent is produced by a conventional method of formulation such as compounding the compound of the present invention, a salt thereof, or a solvate thereof, and adding an appropriate additive as necessary. can do.

Examples of the dosage form of the antifungal agent comprising the compound of the present invention as a salt thereof or a solvate thereof include tablets, powders, granules, or capsules, solutions, syrups, elixirs, or oily or aqueous. Can be exemplified as an oral preparation.
As injections, stabilizers, preservatives, or solubilizing agents may be used in the preparation. After storing a solution that may contain these adjuvants in a container, use as a solid preparation by lyophilization or the like. It may be a preparation for preparation.
Examples of the preparation for external use include solutions, suspensions, emulsions, ointments, gels, creams, lotions, and sprays.
The solid preparation may contain a pharmaceutically acceptable additive together with the compound of the present invention, a salt thereof, or a solvate thereof. For example, fillers, extenders, binders, disintegrants Further, dissolution promoters, wetting agents, lubricants and the like can be selected and mixed as necessary to prepare a formulation.
Examples of liquid preparations include solutions, suspensions, emulsions, etc., but additives may include suspending agents, emulsifiers, and the like.

The method of administering the compound of the present invention, a salt thereof, or a solvate thereof to an animal can be administered directly or mixedly in a feed and orally administered. Examples of such a method include the method of adding to and administering orally, the method of administering by injection, and the like.
As a preparation for administering the compound of the present invention, a salt thereof, or a solvate thereof to an animal, a powder, a fine granule, a soluble powder, or a syrup is appropriately used according to a technique usually used in this field. , Solution or injection.

  In the following, the present invention is illustrated by examples.

[Reference Example 1]
Methyl 5-bromo-4-fluoro-2-hydroxybenzoate (I-1)
4-Fluoro-2-hydroxybenzoic acid (7.51 g, 48.08 mmol) was dissolved in acetic acid (100 ml), and a solution of bromine (2.6 ml, 50.49 mmol) in acetic acid (50 ml) was added dropwise thereto at room temperature. For 16 hours. Furthermore, it stirred at 60 degreeC for 4 hours. The solvent was concentrated under reduced pressure, and water was added to the resulting residue to precipitate crystals. The precipitate was collected by filtration while washing with water, washed with n-hexane, and dried under reduced pressure at 40 ° C., to give 9.51 g (84%) of 5-bromo-4-fluoro-2-hydroxybenzoic acid. Obtained as a brown solid. Part of the obtained bromo compound (3.00 g, 12.77 mmol) was dissolved in methanol (60 ml), concentrated sulfuric acid (6 ml) was added, and the mixture was heated to reflux for 16 hours. The reaction solution was allowed to cool, and the solvent was concentrated under reduced pressure. The obtained residue was dissolved in water and extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography, eluting with a mixed solvent of n-hexane-ethyl acetate (9: 1, v / v) to give 2.87 g (90%) of the title compound. ) Was obtained as a white solid.
MS (FAB) m / z: 250 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 3.96 (3H, s), 6.77 (1H, d, J = 9.5 Hz), 8.05 (1H, d, J = 8.1 Hz), 10 .91 (1H, d, J = 1.7 Hz).

[Reference Example 2]
Methyl 6-fluoro-4-hydroxybiphenyl-3-carboxylate (I-2)
Methyl 5-bromo-4-fluoro-2-hydroxybenzoate (I-1) (2.87 g, 11.54 mmol) was dissolved in tetrahydrofuran (57 ml) under a nitrogen atmosphere, and phenylboronic acid (1.55 g) was dissolved at room temperature. , 12.70 mmol), tripotassium phosphate (4.90 g, 23.08 mmol) and tetrakis (triphenylphosphine) palladium (0) (133 mg, 0.12 mmol). Heated to reflux for 16 hours and cooled to room temperature. The insoluble material was removed by filtration with washing with ethyl acetate, and the filtrate was fractionated with ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, eluted with a mixed solvent of n-hexane-ethyl acetate (10: 1, v / v), 2.37 g (83%) of the title compound. Was obtained as a yellow oil.
MS (ESI) m / z: 247 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 3.96 (3H, s), 6.78 (1H, d, J = 11.7 Hz), 7.36-7.50 (5H, m), 7.95 (1H, d, J = 8.8 Hz), 10.92 (1H, d, J = 1.5 Hz).

[Reference Example 3]
Methyl 6-fluoro-4-hydroxy-5-iodobiphenyl-3-carboxylate (I-3)
Under a nitrogen atmosphere, methyl 6-fluoro-4-hydroxybiphenyl-3-carboxylate (I-2) (2.37 g, 9.61 mmol) was dissolved in a mixture of dichloromethane (100 ml) and methanol (25 ml), and benzyltrimethyl Ammonium dichloroiodate (4.01 g, 11.53 mmol) and sodium hydrogen carbonate (5.24 g, 62.43 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The insoluble material was removed by filtration through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in chloroform, washed with a saturated aqueous ammonium chloride solution, a sodium thiosulfate aqueous solution and a saturated saline solution in this order, and dried using anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, eluting with a mixed solvent of n-hexane-ethyl acetate (5: 1, v / v) to give 3.49 g (98%) of the title compound. ) Was obtained as a light brown solid.
MS (ESI) m / z: 371 (M-1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 4.00 (3H, s), 7.36-7.49 (5H, m), 7.97 (1H, d, J = 8.5 Hz), 11.86 (1H, d, J = 2.2 Hz).

[Reference Example 4]
Methyl 6-fluoro-5-iodo-4-methoxybiphenyl-3-carboxylate (I-4)
Methyl 6-fluoro-4-hydroxy-5-iodobiphenyl-3-carboxylate (I-3) (2.00 g, 5.37 mmol) was dissolved in acetonitrile (40 ml) under a nitrogen atmosphere, and potassium carbonate (891 mg, 6.45 mmol) and dimethyl sulfate (560 μl, 5.91 mmol) were added, and the mixture was stirred at 60 ° C. for 15 hours. Diethyl ether was added to the reaction solution, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography eluting with a mixed solvent of n-hexane-ethyl acetate (5: 1, v / v) to give 2.10 g (quant. ) Was obtained as a colorless transparent oily substance.
MS (ESI) m / z: 387 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 3.94 (3H, s), 3.96 (3H, s), 7.40-7.52 (5H, m), 7.97 (1H, d, J = 8.8 Hz).

[Reference Example 5]
6-Fluoro-5-iodo-4-methoxybiphenyl-3-carboxylic acid (I-5)
Methyl 6-fluoro-5-iodo-4-methoxybiphenyl-3-carboxylate (I-4) (742.7 mg, 1.92 mmol) was dissolved in methanol (7.5 ml), and 1N aqueous sodium hydroxide solution ( 2.2 ml) was added and heated to reflux for 3 hours. After allowing the reaction to cool, the solvent was concentrated under reduced pressure and fractionated with water and ethyl acetate. A 1N aqueous hydrochloric acid solution was added to the aqueous layer to make it acidic (pH 1), and the resulting organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to obtain 683.5 mg (96%) of the title compound as a white solid.
MS (ESI) m / z: 373 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 4.06 (3H, s), 7.42-7.53 (5H, m), 8.23 (1H, d, J = 8.8 Hz).

[Reference Example 6]
6-Fluoro-5-iodo-4-methoxybiphenyl-3-carboxamide (I-6)
6-Fluoro-5-iodo-4-methoxybiphenyl-3-carboxylic acid (I-5) (1.91 g, 5.13 mmol) was dissolved in dichloromethane (20 ml) under a nitrogen atmosphere. One drop of N-dimethylformamide and oxalyl chloride (660 μl, 7.69 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The solvent was concentrated under reduced pressure and azeotroped twice with benzene. The obtained residue was dissolved in ethyl acetate (40 ml), 28% aqueous ammonium solution (20 ml) was added under ice cooling, and the mixture was stirred at 0 ° C. for 5 hr. The reaction solution was washed with 1N hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to obtain 1.56 g (82%) of the title compound as a white solid.
MS (ESI) m / z: 372 (M + 1) ^<+> .

[Reference Example 7]
6-Fluoro-5-iodo-4-methoxybiphenyl-3-carbonitrile (I-7)
Under a nitrogen atmosphere, 6-fluoro-5-iodo-4-methoxybiphenyl-3-carboxamide (I-6) (1.56 g, 4.20 mmol) and 4- (dimethylamino) pyridine (25.7 mg, 0.21 mmol) ) Was dissolved in pyridine (16 ml), trifluoromethanesulfonic anhydride (1.48 ml, 8.83 mmol) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in ethyl acetate. Fractionated with 1N aqueous hydrochloric acid, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, the obtained residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of n-hexane-ethyl acetate (5: 1, v / v) to give 1.54 g (quant. ) Was obtained as a white solid.
MS (FAB) m / z: 354 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 4.15 (3H, s), 7.43-7.50 (5H, m), 7.66 (1H, d, J = 8.1 Hz).
IR (ATR): 2229, 1465, 1423, 1043 cm ⁻¹ .

[Reference Example 8]
6-Fluoro-5- (2-fluoropyridin-3-yl) -4-methoxybiphenyl-3-carbonitrile (I-8)
6-Fluoro-5-iodo-4-methoxybiphenyl-3-carbonitrile (I-7) (1.05 g, 2.96 mmol), 2-fluoro-3- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) pyridine (793 mg, 3.55 mmol) and cesium carbonate (1.45 g, 4.44 mmol) were suspended in toluene (20 ml), and tetrakis ( Triphenylphosphine) palladium (0) (171 mg, 0.15 mmol) was added and stirred at 80 ° C. for 15 hours. Since the reaction was not completed, tetrakistriphenylphosphine palladium (0) (171 mg, 0.15 mmol) was added and heated to reflux for 4 hours, but the reaction did not proceed. The reaction solution was allowed to cool to room temperature, washed with ethyl acetate, insolubles were filtered off through celite, and the filtrate was fractionated with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating the solvent under reduced pressure was subjected to silica gel column chromatography, eluting with a mixed solvent of n-hexane-ethyl acetate (5: 1, v / v) to obtain 284 mg (30%) of the title compound. Obtained as a yellow clear oil. In addition, 512 mg (49%) of unreacted iodine material (I-7) was recovered.
MS (ESI) m / z: 323 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 3.94 (3H, s), 7.34 (1H, ddd, J = 2.0, 4.9, 7.1 Hz), 7.41-7.52 ( 6H, m), 7.76 (1H, d, J = 8.1 Hz), 7.83 (1H, ddd, J = 2.0, 7.3, 9.3 Hz), 8.34 (1H, d , J = 4.2 Hz).

[Reference Example 9]
5-Fluoro-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-9)
Aluminum chloride (III) (122 mg, 0.92 mmol) was dissolved in benzene (5 ml) under a nitrogen stream, and 6-fluoro-5- (2-fluoropyridin-3-yl) -4-methoxybiphenyl-3-carbohydrate was dissolved. A benzene solution (5 ml) of nitrile (I-8) (134 mg, 0.42 mmol) was added, and the mixture was heated to reflux for 16 hours. The mixture was allowed to cool to room temperature, and the reaction mixture was fractionated with ethyl acetate and dilute aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to obtain 6-fluoro-5- (2-fluoropyridin-3-yl) -4-hydroxybiphenyl-3-carbonitrile (127 mg, 99%) as a yellow transparent oily substance. Along with 6-fluoro-5- (2-fluoropyridin-3-yl) -4-hydroxybiphenyl-3-carbonitrile obtained by the same method, (153 mg, 0.50 mmol) was dissolved in acetonitrile (6 ml). Then, potassium carbonate (82.4 mg, 0.60 mmol) was added, and the mixture was heated to reflux for 20 hours. The reaction was allowed to cool, insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of n-hexane-ethyl acetate (5: 1, v / v) to obtain 82 mg (58%) of the title compound as a white solid.
MS (ESI) m / z: 289 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 7.45-7.60 (6H, m), 7.89 (1H, d, J = 7.1 Hz), 8.45 (1H, dd, J = 1. 7, 7.6 Hz), 8.60 (1H, dd, J = 1.7, 4.9 Hz).

[Example 1]
5-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (# 1)

窒素雰囲気下に５−フルオロ−６−フェニル［１］ベンゾフロ［２，３−ｂ］ピリジン−８−カルボニトリル（Ｉ−９）（８２ｍｇ，０．２９ｍｍｏｌ）をジメチルスルホキシド（２．６ｍｌ）に溶解させ、トリエチルアミン（９２μｌ，０．６６ｍｍｏｌ）および（３Ｓ）−３−（ジメチルアミノ）ピロリジン（４７μｌ，０．３７ｍｍｏｌ）を加え、９０℃にて１７時間撹拌した。反応液を放冷し、クロロホルムを加え、水および飽和食塩水で洗浄し、無水硫酸ナトリウムを用いて乾燥した。溶媒を留去して得られた残留物をプレパラティブＴＬＣ（クロロホルム：メタノール＝２０：１，ｖ／ｖ）を用いて精製した。ｎ−ヘキサン、酢酸エチルおよびジエチルエーテルの混合溶媒にて再結晶し、標記化合物４９ｍｇ（４４％）を白色固体として得た。

Dissolve 5-fluoro-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-9) (82 mg, 0.29 mmol) in dimethyl sulfoxide (2.6 ml) under a nitrogen atmosphere. Triethylamine (92 μl, 0.66 mmol) and (3S) -3- (dimethylamino) pyrrolidine (47 μl, 0.37 mmol) were added, and the mixture was stirred at 90 ° C. for 17 hours. The reaction mixture was allowed to cool, chloroform was added, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified using preparative TLC (chloroform: methanol = 20: 1, v / v). Recrystallization from a mixed solvent of n-hexane, ethyl acetate and diethyl ether gave 49 mg (44%) of the title compound as a white solid.

mp: 171-173 ° C.
MS (ESI) m / z: 383 (M + 1) ^<+> .
¹ H-NMR (DMSO-d ₆ ) δ: 1.74-1.83 (1H, m), 2.04-2.08 (1H, m), 2.13 (6H, s), 2.95 (2H, brs), 3.16-3.20 (3H, m), 7.37-7.50 (5H, m), 7.60 (1H, dd, J = 4.9, 7.8 Hz) ), 7.67 (1H, s), 8.28 (1H, dd, J = 1.5, 7.6 Hz), 8.50 (1H, dd, J = 1.7, 4.9 Hz).
IR (ATR): 2227, 1469, 1389 cm ⁻¹ .
Anal. _{Calcd for C 24 H 22 N 4} O · 0.5H 2 O: C, 73.64; H, 5.92; N, 14.31. Found: C, 73.62; H, 5.75; N, 14.25.

[Example 2]
5-[(3S) -3- (methylamino) pyrrolidin-1-yl] -6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (# 2)

  To a suspension of 5-fluoro-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-9) (550 mg, 2.40 mmol) in dimethyl sulfoxide (11 ml) was added (3S). -3- (Methylamino) pyrrolidine (0.33 ml, 3.1 mmol) and triethylamine (0.84 ml, 6.00 mmol) were added and stirred at 90 ° C. for 15 and a half hours. At this time, the reaction solution became uniform as the temperature increased. After allowing to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the portion eluted with chloroform-methanol (50: 1, v / v) was concentrated under reduced pressure. The residue was suspended and washed with diethyl ether and dried. This gave 511 mg (58%) of the title compound as a yellow solid.

mp: 151-153 ° C
MS (FAB) m / z: 369 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 1.36 (1H, brs), 1.68-1.78 (1H, m), 2.11-2.22 (1H, m), 2.38 (3H , S), 2.92 (1H, dd, J = 4.5, 9.9 Hz), 3.06-3.21 (2H, m), 3.24-3.33 (2H, m), 7 .29-7.32 (2H, m), 7.39-7.49 (4H, m), 7.56 (1H, s), 8.27 (1H, dd, J = 1.5,7. 5 Hz), 8.49 (1H, dd, J = 1.5, 4.8 Hz).
IR (diffuse reflectance spectroscopy): 2840, 2225, 1598, 1473, 1398 cm ⁻¹ .
Anal. _{Calcd for C 23 H 20 N 4} O · 0.25H 2 O: C, 74.07; H, 5.54; N, 15.02. Found: C, 74.12; H, 5.35; N, 15.04.

[Example 3]
6-Phenyl-5- (piperazin-1-yl) [1] benzofuro [2,3-b] pyridine-8-carbonitrile (# 3)
To a suspension of 5-fluoro-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-9) (180 mg, 0.79 mmol) in dimethyl sulfoxide (4 ml) was added anhydrous piperazine ( 89 mg, 1.03 mmol) and triethylamine (0.28 ml, 2.00 mmol) were added and stirred at 90 ° C. for 16 and a half hours. At this time, the reaction solution became uniform as the temperature increased. After allowing to cool to room temperature, water was added to the reaction solution, the precipitated solid was collected by filtration, and the resulting solid was suspended and washed with diethyl ether and dried to obtain 91 mg (33%) of the title compound as a light brown solid. .
mp: 264-269 ° C. (dec.)
MS (FAB) m / z: 355 (M + 1) ^<+> .
¹ H-NMR (DMSO-d ₆ ) δ: 2.79 (8H, s), 7.35-7.38 (2H, m), 7.42-7.52 (4H, m), 7.64 -7.68 (1H, m), 7.76 (1H, s), 8.55 (1H, d, J = 6.0 Hz).
IR (diffuse reflectance spectroscopy): 2813, 2229, 1596, 1391, 1232 cm ⁻¹ .
Anal. _{Calcd for C 22 H 18 N 4} O · 1.25H 2 O: C, 70.10; H, 5.48; N, 14.86. Found: C, 69.90; H, 5.20; N, 14.18.

[Example 4]
N-methyl-1- (6-phenyl [1] benzofuro [2,3-b] pyridin-5-yl) azetidin-3-amine (# 4)

  To a suspension of 5-fluoro-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-9) (550 mg, 2.40 mmol) in dimethyl sulfoxide (11 ml) was added 3- ( Methylamino) azetidine ditrifluoroacetate (734 mg, 2.34 mmol) and triethylamine (1.70 ml, 12.0 mmol) were added and stirred at 90 ° C. for 16 hours. At this time, the reaction solution became uniform as the temperature increased. After allowing to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the portion eluted with chloroform-methanol (25: 1, v / v) was concentrated under reduced pressure. The residue was suspended and washed with diethyl ether and dried. This gave 570 mg (67%) of the title compound as a pale yellow solid.

mp: 170-172 ° C
MS (FAB) m / z: 355 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 1.45 (1H, brs), 2.31 (3H, s), 3.37-3.45 (1H, m), 3.65 (2H, dd, J = 4.8, 9.0 Hz), 4.08 (2 H, dd, J = 8.1, 9.0 Hz), 7.31-7.45 (6 H, m), 7.50 (1 H, s) , 8.12 (1H, dd, J = 1.5, 7.8 Hz), 8.38 (1H, dd, J = 1.5, 4.8 Hz).
IR (diffuse reflectance spectroscopy): 3316,2942,2851,210,1613,1450,1397 cm ⁻¹ .
Anal. _{Calcd for C 22 H 18 N 4} O · 0.25H 2 O: C, 73.62; H, 5.20; N, 15.61. Found: C, 73.59; H, 5.01; N, 15.35.

[Example 5]
N, N-dimethyl-1- (6-phenyl [1] benzofuro [2,3-b] pyridin-5-yl) azetidin-3-amine (# 5)
N-methyl-1- (6-phenyl [1] benzofuro [2,3-b] pyridin-5-yl) azetidin-3-amine (# 4) (200 mg, 0.56 mmol) in tetrahydrofuran (15 ml) and dichloromethane (15 ml) was dissolved in a mixed solution, 36% aqueous formaldehyde solution (0.28 ml, 2.80 mmol) and sodium triacetoxyborohydride (593 mg, 2.80 mmol) were added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the residue obtained was subjected to column chromatography, and the portion eluted with chloroform-methanol (50: 1, v / v) was concentrated under reduced pressure. The residue was suspended and washed with diethyl ether, and then dried. This gave 181 mg (88%) of the title compound as a pale yellow solid.

mp: 180-182 ° C
MS (FAB) m / z: 369 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.04 (6H, s), 2.84-2.92 (1H, m), 3.70 (2H, dd, J = 5.1, 9.0 Hz) , 4.00 (2H, t, J = 8.4 Hz), 7.32-7.45 (6H, m), 7.52 (1H, s), 8.11 (1H, dd, J = 1. 5,7.8 Hz), 8.40-8.42 (1H, m).
IR (diffuse reflectance spectroscopy): 2947, 2206, 1611, 1556, 1495, 1445 cm ⁻¹ .
Anal. _{Calcd for C 23 H 20 N 4} O: C, 74.98; H, 5.47; N, 15.21. Found: C, 74.56; H, 5.47; N, 14.83.

[Reference Example 10]
Methyl 6-fluoro-4-hydroxy-2'-methylbiphenyl-3-carboxylate (I-10)
Methyl 5-bromo-4-fluoro-2-hydroxybenzoate (I-1) (990 mg, 3.98 mmol) was dissolved in tetrahydrofuran (20 ml) under a nitrogen atmosphere, and 2-methylphenylboronic acid (595 mg, 4.37 mmol), tripotassium phosphate (1.69 g, 7.95 mmol) and tetrakis (triphenylphosphine) palladium (0) (46 mg, 0.04 mmol) were added. Heated to reflux for 11 hours and cooled to room temperature. The insoluble material was removed by filtration with washing with ethyl acetate, and the filtrate was fractionated with diethyl ether and saturated aqueous ammonium chloride. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography eluting with a mixed solvent of n-hexane-ethyl acetate (8: 1, v / v) to give 784.6 mg (76%) of the title compound. ) Was obtained as a colorless transparent oily substance.
MS (ESI) m / z: 261 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 2.19 (3H, s), 3.93 (3H, s), 6.76 (1H, d, J = 10.7 Hz), 7.17-7.30 (6H, m), 7.78 (1H, d, J = 8.5 Hz), 10.95 (1H, d, J = 1.5 Hz).

[Reference Example 11]
Methyl 6-fluoro-4-hydroxy-5-iodo-2′-methylbiphenyl-3-carboxylate (I-11)
Dissolve methyl 6-fluoro-4-hydroxy-2′-methylbiphenyl-3-carboxylate (I-10) (784 mg, 3.01 mmol) in a mixed solution of dichloromethane (32 ml) and methanol (8 ml) under a nitrogen atmosphere. Benzyltrimethylammonium dichloroiodate (1.26 g, 3.62 mmol) and sodium hydrogen carbonate (1.64 g, 19.58 mmol) were added, and the mixture was stirred at room temperature for 18 hours. The insoluble material was removed by filtration through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in chloroform, washed with a saturated aqueous solution of ammonium chloride, a saturated aqueous solution of sodium thiosulfate and a saturated saline solution in that order, and dried using anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, eluting with a mixed solvent of n-hexane-ethyl acetate (5: 1, v / v) to give 1.03 g (89%) of the title compound. ) Was obtained as a pale yellow oil.
¹ H-NMR (CDCl ₃ ) δ: 2.18 (3H, s), 3.97 (3H, d, J = 10.7 Hz), 7.16 (1H, d, J = 7.1 Hz), 7 .22-7.32 (8H, m), 7.81 (1H, d, J = 8.3 Hz), 11.86 (1H, d, J = 2.2 Hz).

[Reference Example 12]
Methyl 6-fluoro-5-iodo-4-methoxy-2′-methylbiphenyl-3-carboxylate (I-12)
Methyl 6-fluoro-4-hydroxy-5-iodo-2′-methylbiphenyl-3-carboxylate (I-11) (1.03 g, 2.68 mmol) was dissolved in acetonitrile (20 ml) under a nitrogen atmosphere, Potassium carbonate (444 mg, 3.21 mmol) and dimethyl sulfate (279 μl, 2.94 mmol) were added, and the mixture was stirred at 60 ° C. for 14 hours. The insoluble material was filtered through Celite, ethyl acetate was added to the filtrate, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water and saturated brine in that order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to obtain 1.03 g (97%) of the title compound as a pale yellow transparent oily substance.
MS (ESI) m / z: 401 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 2.19 (3H, s), 3.92 (3H, s), 3.98 (3H, s), 7.17 (1H, d, J = 7.3 Hz) ), 7.23-7.34 (4H, m), 7.80 (1H, d, J = 8.5 Hz).

[Reference Example 13]
6-Fluoro-5-iodo-4-methoxy-2'-methylbiphenyl-3-carboxylic acid (I-13)
Methyl 6-fluoro-5-iodo-4-methoxy-2′-methylbiphenyl-3-carboxylate (I-12) (1.03 g, 2.60 mmol) was dissolved in methanol (10 ml), and 1N hydroxide was added. A sodium aqueous solution (2.7 ml) was added, and the mixture was heated to reflux for 20 hours. After allowing the reaction to cool, the solvent was concentrated under reduced pressure and fractionated with water and n-hexane. The aqueous layer was acidified with 1N aqueous hydrochloric acid (pH = 1), extracted with ethyl acetate, and the resulting organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to obtain 943 mg (94%) of the title compound as a white solid.
MS (ESI) m / z: 387 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.19 (3H, s), 4.07 (3H, s), 7.17 (1H, d, J = 7.3 Hz), 7.26-7.35 (5H, m), 8.04 (1H, d, J = 8.3 Hz).

[Reference Example 14]
6-Fluoro-5-iodo-4-methoxy-2′-methylbiphenyl-3-carboxamide (I-14)
Under a nitrogen atmosphere, 6-fluoro-5-iodo-4-methoxy-2′-methylbiphenyl-3-carboxylic acid (I-13) (943 mg, 2.44 mmol) was dissolved in dichloromethane (9 ml), and ice-cooled. To the solution, 1 drop of N, N-dimethylformamide and oxalyl chloride (314 μl, 3.66 mmol) were added, and the mixture was stirred at room temperature for 23 hours. Since the raw material remained, the mixture was further heated to reflux for 2 hours. After allowing to cool, the solvent was concentrated under reduced pressure and azeotroped twice with benzene. The obtained residue was dissolved in ethyl acetate (18 ml), 28% aqueous ammonium solution (9 ml) was added under ice cooling, and the mixture was stirred at 0 ° C. for 2 hr. The reaction solution was washed with 1N hydrochloric acid aqueous solution, water and saturated brine in that order and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to obtain 873 mg (93%) of the title compound as a pale yellow solid.
MS (ESI) m / z: 386 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.18 (3H, s), 3.96 (3H, s), 5.84 (1H, br s), 7.16-7.34 (7H, m) 7.55 (1H, br s), 8.04 (1H, d, J = 8.5 Hz).

[Reference Example 15]
6-Fluoro-5-iodo-4-methoxy-2′-methylbiphenyl-3-carbonitrile (I-15)
Under a nitrogen atmosphere, 6-fluoro-5-iodo-4-methoxy-2′-methylbiphenyl-3-carboxamide (I-14) (873 mg, 2.27 mmol) and 4- (dimethylamino) pyridine (13.8 mg, 0.11 mmol) was dissolved in pyridine (8.7 ml), trifluoromethanesulfonic anhydride (458 μl, 2.72 mmol) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in ethyl acetate. Fractionated with 1N aqueous hydrochloric acid, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, eluting with a mixed solvent of n-hexane-ethyl acetate (10: 1, v / v) to give 759 mg (91%) of the title compound. Obtained as a pale yellow clear oil.
MS (FAB) m / z: 368 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.18 (3H, s), 4.17 (3H, s), 7.13 (1H, d, J = 7.6 Hz), 7.25-7.37 (4H, m), 7.50 (1H, d, J = 7.8 Hz).
IR (ATR): 2229, 1466, 1423 cm ⁻¹ .

[Reference Example 16]
6-Fluoro-5- (2-fluoropyridin-3-yl) -4-methoxy-2'-methylbiphenyl-3-carbonitrile (I-16)
6-Fluoro-5-iodo-4-methoxy-2′-methylbiphenyl-3-carbonitrile (I-15) (758 mg, 2.06 mmol), 2-fluoro-3- (4,4,5,5- Tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (553 mg, 2.48 mmol) and cesium carbonate (1.01 g, 3.10 mmol) were suspended in toluene (15 ml) and brought to room temperature under a nitrogen stream. Tetrakis (triphenylphosphine) palladium (0) (119 mg, 0.10 mmol) was added, and the mixture was stirred at 90 ° C. for 17 hours. The reaction solution was allowed to cool to room temperature, washed with ethyl acetate, insolubles were filtered off through celite, and the filtrate was fractionated with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating the solvent under reduced pressure was subjected to silica gel column chromatography, eluting with a mixed solvent of n-hexane-ethyl acetate (5: 1, v / v) to obtain 330 mg (48%) of the title compound. Obtained as a yellow clear oil.
MS (ESI) m / z: 337 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.23 (3H, s), 3.95 (3H, s), 7.20 (1H, d, J = 7.6 Hz), 7.27-7.37 (4H, m), 7.59 (1H, d, J = 7.8 Hz), 7.84 (1H, ddd, J = 2.1, 7.3, 9.3 Hz), 8.33 (1H, dt, J = 0.9, 4.9 Hz).

[Reference Example 17]
5-Fluoro-6- (2-methylphenyl) [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-17)
Aluminum chloride (III) (275 mg, 2.06 mmol) was dissolved in benzene (6.6 ml) under a nitrogen stream, and 6-fluoro-5- (2-fluoropyridin-3-yl) -4-methoxy-2 ′ was dissolved. -A benzene solution (3 ml) of methylbiphenyl-3-carbonitrile (I-16) (330 mg, 0.98 mmol) was added, and the mixture was heated to reflux for 19 hours. Since the reaction solution became tar-like and unreacted raw materials were confirmed, tetrahydrofuran (2 ml) was added and completely dissolved, aluminum (III) chloride (275 mg, 2.06 mmol) was added, and the mixture was heated to reflux for 21 hours. The mixture was allowed to cool to room temperature, and the reaction mixture was fractionated with ethyl acetate and dilute aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to obtain 6-fluoro-5- (2-fluoropyridin-3-yl) -4-hydroxy-2′-methylbiphenyl-3-carbonitrile as a pale yellow transparent oily substance. The obtained hydroxy form was dissolved in acetonitrile (4.7 ml), potassium carbonate (60.7 mg, 0.44 mmol) was added, and the mixture was heated to reflux for 19 hours. The reaction was allowed to cool, insoluble material was filtered off through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of n-hexane-ethyl acetate (3: 1, v / v) to obtain 79 mg (27%) of the title compound as a pale yellow solid. .
MS (ESI) m / z: 303 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.24 (3H, s), 7.23-7.42 (4H, m), 7.49 (1H, dd, J = 4.9, 7.6 Hz) 7.72 (1H, d, J = 6.6 Hz), 8.43 (1H, dd, J = 1.7, 7.6 Hz), 8.60 (1H, dd, J = 1.7, 4) .9 Hz).

[Example 6]
5-[(3S) -3- (dimethylamino) pyrrolidinyl] -6- (2-methylphenyl) [1] benzofuro [2,3-b] pyridine-8-carbonitrile (# 6)
Under a nitrogen atmosphere, 5-fluoro-6- (2-methylphenyl) [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-17) (78 mg, 0.26 mmol) was added to dimethyl sulfoxide (2 4 ml), triethylamine (83 μl, 0.59 mmol) and (3S) -3- (dimethylamino) pyrrolidine (43 μl, 0.34 mmol) were added, and the mixture was stirred at 90 ° C. for 25 hours. The reaction mixture was allowed to cool, chloroform was added, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified using preparative TLC (chloroform: methanol = 20: 1, v / v). Recrystallization from a mixed solvent of n-hexane-ethyl acetate-diethyl ether gave 18 mg (18%) of the title compound as a yellow solid.

mp: 161-163 ° C
MS (ESI) m / z: 397 (M + 1) ⁺ .
¹ H-NMR (DMSO-d ₆ ) δ: 1.65-1.73 (1H, m), 2.06 (4H, s), 2.12 (3H, d, J = 6.8 Hz), 2 .74-2.86 (2H, m), 3.03-3.16 (6H, m), 7.18 (1H, t, J = 8.8 Hz), 7.24-7.28 (1H, m), 7.34 (2H, d, J = 4.6 Hz), 7.57-7.61 (2H, m), 8.24 (1H, m), 8.50 (1H, d, J = 4.9 Hz).
IR (ATR): 2224, 1464, 1387, 1358, 1161 cm ⁻¹ .
Anal. _{Calcd for C 25 H 24 N 4} O · 0.5H 2 O: C, 74.05; H, 6.21; N, 13.84. Found: C, 74.11; H, 6.10; N, 14.13.

[Reference Example 18]
Methyl 3 ′-(benzyloxy) -6-fluoro-4-hydroxybiphenyl-3-carboxylate (I-18)
Under a nitrogen atmosphere, methyl 5-bromo-4-fluoro-2-hydroxybenzoate (I-1) (4.60 g, 18.5 mmol), 3-benzyloxyphenylboronic acid (5.05 g, 22.2 mmol), phosphorus A suspension of tripotassium acid (7.85 g, 37.0 mmol) and tetrakis (triphenylphosphine) palladium (0) (1.07 g, 925 μmol) in 1,4-dioxane (93 ml) was heated to reflux for 16 hours. After cooling, the reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 2.35 g (36%) of the title compound was obtained as a yellow oil from a fraction eluted with n-hexane-ethyl acetate (8: 1, v / v).
MS (ESI) m / z: 353 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 3.96 (3H, s), 5.11 (2H, s), 6.77 (1H, d, J = 11.7 Hz), 6.96-7.00 (1H, m), 7.08-7.14 (2H, m), 7.31-7.42 (4H, m), 7.44-7.48 (2H, m), 7.95 (1H , D, J = 8.8 Hz), 10.93 (1H, d, J = 1.7 Hz).
IR (ATR): 1674, 1599, 1485, 1441, 1336, 1252, 1213, 1144 cm ⁻¹ .

[Reference Example 19]
Methyl 3 ′-(benzyloxy) -6-fluoro-4-hydroxy-5-iodobiphenyl-3-carboxylate (I-19)
To a mixed solution of methyl 3 ′-(benzyloxy) -6-fluoro-4-hydroxybiphenyl-3-carboxylate (I-18) (2.35 g, 6.67 mmol) in methanol-dichloromethane (17 ml-67 ml) was added benzyl. Trimethylammonium dichloroiodide (2.79 g, 8.00 mmol) and sodium hydrogen carbonate (3.64 g, 43.4 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 2.74 g (86%) of the title compound was obtained as a pale red solid from a fraction eluted with n-hexane-chloroform (1: 1, v / v).
MS (EI) m / z: 478 (M ^<+> ).
¹ H-NMR (CDCl ₃ ) δ: 3.99 (3H, s), 5.11 (2H, s), 6.97-7.02 (1H, m), 7.06-7.12 (2H M), 7.31-7.48 (6H, m), 7.97 (1H, d, J = 8.5 Hz), 11.87 (1H, d, J = 2.2 Hz).
IR (ATR): 1678, 1577, 1435, 1331, 1232, 1215, 1174 cm ⁻¹ .

[Reference Example 20]
Methyl 3 ′-(benzyloxy) -6-fluoro-5-iodo-4-methoxybiphenyl-3-carboxylate (I-20)
Methyl 3 ′-(benzyloxy) -6-fluoro-4-hydroxy-5-iodobiphenyl-3-carboxylate (I-19) (2.74 g, 5.73 mmol), potassium carbonate (950 mg, 6.88 mmol) A suspension of dimethyl sulfate (598 μl, 6.30 mmol) in acetonitrile (57 ml) was stirred at 60 ° C. for 5 hours. After cooling, the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 2.91 g (100%) of the title compound was obtained as a colorless oil from a fraction eluted with n-hexane-ethyl acetate (5: 1, v / v).
MS (ESI) m / z: 493 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 3.94 (3H, s), 3.96 (3H, s), 5.11 (2H, s), 7.00-7.04 (1H, m), 7.08-7.15 (2H, m), 7.31-7.48 (6H, m), 7.97 (1 H, d, J = 8.8 Hz).
IR (ATR): 1728, 1579, 1460, 1423, 1234, 1169, 1049 cm ⁻¹ .

[Reference Example 21]
3 ′-(Benzyloxy) -6-fluoro-5-iodo-4-methoxybiphenyl-3-carboxylic acid (I-21)
To a solution of methyl 3 ′-(benzyloxy) -6-fluoro-5-iodo-4-methoxybiphenyl-3-carboxylate (I-20) (2.91 g, 5.73 mmol) in methanol (29 ml), 1N An aqueous sodium hydroxide solution (6.30 ml, 6.30 mmol) was added, tetrahydrofuran (8 ml) was added, and the mixture was heated to reflux for 2.5 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with water. The aqueous layer was washed with n-hexane, acidified with 1N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure to obtain 2.64 g (96%) of the title compound as a white solid.
MS (ESI) m / z: 479 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 4.04 (3H, s), 5.11 (2H, s), 7.03 (1H, dd, J = 8.3, 2.4 Hz), 7.09 -7.15 (2H, m), 7.31-7.48 (6H, m), 8.20 (1H, d, J = 8.8 Hz).
IR (ATR): 1703, 1674, 1589, 1462, 1421, 1377, 1311, 1290, 1248, 1188 cm ⁻¹ .

[Reference Example 22]
3 ′-(Benzyloxy) -6-fluoro-5-iodo-4-methoxybiphenyl-3-carboxamide (I-22)
3 '-(Benzyloxy) -6-fluoro-5-iodo-4-methoxybiphenyl-3-carboxylic acid (I-21) (2.64 g, 5.52 mmol) in N, N-dimethylformamide (55 ml) 1-hydroxybenzotriazole (895 mg, 6.62 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1.27 g, 6.62 mmol) and 28% aqueous ammonia at room temperature. 1.01 ml (16.6 mmol) was added and stirred for 20 hours. After the reaction solution was concentrated under reduced pressure, the resulting residue was dissolved in chloroform, and the organic layer was washed with 1N aqueous hydrochloric acid. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was suspended and washed in acetonitrile to give 1.78 g of the title compound as a white solid. The residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography to obtain 548 mg of the title compound from the eluate of n-hexane-ethyl acetate (1: 1, v / v). .33 g (88%) was obtained.
MS (ESI) m / z: 478 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 3.94 (3H, s), 5.11 (2H, s), 5.84 (1H, brs), 6.99-7.03 (1H, m), 7.10-7.17 (2H, m), 7.32-7.36 (2H, m), 7.37-7.42 (2H, m), 7.44-7.47 (2H, m) ), 7.54 (1H, brs), 8.23 (1H, d, J = 8.8 Hz).
IR (ATR): 3390, 3178, 1639, 1577, 1450, 1414, 1244, 1188 cm ⁻¹ .

[Reference Example 23]
3 ′-(Benzyloxy) -6-fluoro-5-iodo-4-methoxybiphenyl-3-carbonitrile (I-23)
Under a nitrogen atmosphere, 3 ′-(benzyloxy) -6-fluoro-5-iodo-4-methoxybiphenyl-3-carboxamide (I-22) (1.78 g, 3.73 mmol) and 4- (dimethylamino) pyridine To a pyridine (15 ml) solution of (23 mg, 187 μmol), trifluoromethanesulfonic anhydride (941 μl, 5.59 mmol) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in ethyl acetate, and the organic layer was washed with 1N aqueous hydrochloric acid solution, water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 1.52 g (89%) of the title compound was obtained as a pale red solid from a fraction eluted with n-hexane-ethyl acetate (3: 1, v / v).
MS (EI) m / z: 459 (M ^<+> ).
¹ H-NMR (CDCl ₃ ) δ: 4.15 (3H, s), 5.11 (2H, s), 7.02-7.08 (3H, m), 7.32-7.47 (6H) , M), 7.65 (1H, d, J = 7.8 Hz).
IR (ATR): 2227, 1595, 1469, 1417, 1255, 1238 cm ⁻¹ .

[Reference Example 24]
3 ′-(Benzyloxy) -6-fluoro-5- (2-fluoropyridin-3-yl) -4-methoxybiphenyl-3-carbonitrile (I-24)
Under a nitrogen atmosphere, 3 ′-(benzyloxy) -6-fluoro-5-iodo-4-methoxybiphenyl-3-carbonitrile (I-23) (500 mg, 1.09 mmol), 2-fluoro-3- (4 , 4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) pyridine (291 mg, 1.31 mmol), cesium carbonate (710 mg, 2.18 mmol) and tetrakis (triphenylphosphine) palladium (0 ) (63 mg, 55 μmol) in toluene (11 ml) was stirred at 100 ° C. for 22 hours. After cooling, the reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 195 mg (42%) of the title compound was obtained as a yellow oil from a fraction eluted with n-hexane-ethyl acetate (3: 1, v / v).
MS (ESI) m / z: 429 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 3.94 (3H, s), 5.11 (2H, s), 7.02-7.06 (1H, m), 7.07-7.13 (2H , M), 7.31-7.47 (6H, m), 7.57-7.63 (1H, m), 7.74 (1H, d, J = 8.1 Hz), 7.80-7 .85 (1H, m), 8.32-8.35 (1H, m).
IR (ATR): 2229, 1572, 1473, 1419, 1396, 1244, 1215, 1161 cm ⁻¹ .

[Reference Example 25]
6- [3- (Benzyloxy) phenyl] -5-fluoro [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-25)
3 '-(Benzyloxy) -6-fluoro-5- (2-fluoropyridin-3-yl) -4-methoxybiphenyl-3-carbonitrile (I-24) (422 mg, 985 μmol) and triethylamine under nitrogen atmosphere A solution of (412 μl, 2.95 mmol) in dimethyl sulfoxide (10 ml) was stirred at 130 ° C. for 17.5 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform. Next, the organic layer was washed with water, and then the aqueous layer was extracted with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 215 mg (55%) of the title compound was obtained as a pale yellow solid from a fraction eluted with n-hexane-ethyl acetate (4: 1, v / v).
MS (ESI) m / z: 395 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 5.15 (2H, s), 7.06-7.11 (1H, m), 7.15-7.20 (2H, m), 7.33-7 .52 (7H, m), 7.88 (1H, d, J = 6.8 Hz), 8.44 (1H, dd, J = 7.7, 1.6 Hz), 8.60 (1H, dd, J = 4.9, 1.6 Hz).
IR (ATR): 2231, 1593, 1487, 1390, 1350, 1281, 1227 cm ⁻¹ .

[Example 7]
6- [3- (Benzyloxy) phenyl] -5-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] [1] benzofuro [2,3-b] pyridine-8-carbonitrile (# 7)
Under a nitrogen atmosphere, 6- [3- (benzyloxy) phenyl] -5-fluoro [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-25) (228 mg, 578 μmol)), triethylamine ( A solution of 242 μl, 1.73 mmol) and (3S) -3- (dimethylamino) pyrrolidine (147 μl, 1.16 mmol) in dimethyl sulfoxide (6 ml) was stirred at 90 ° C. for 18 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform. Next, the organic layer was washed with saturated aqueous sodium hydrogen carbonate, and the aqueous layer was extracted with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give the title compound from the eluate of dichloromethane-methanol (30: 1, v / v), and a part of the title compound was suspended and washed with diisopropyl ether. 22 mg (8%) was obtained as a light brown solid. Further, 185 mg of the rest was obtained as amorphous, and 207 mg (73%) of the title compound was obtained in total.

mp: 167-170 ° C.
MS (ESI) m / z: 489 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 1.75-1.88 (1H, m), 2.06-2.21 (1H, m), 2.19 (6H, s), 2.65-2 .75 (1H, m), 3.02-3.24 (4H, m), 5.13 (2H, s), 6.87-6.92 (2H, m), 7.01-7.06 (1H, m), 7.33-7.47 (7H, m), 7.56 (1H, s), 8.15 (1H, d, J = 7.6 Hz), 8.51 (1H, dd) , J = 4.9, 1.5 Hz).
Anal. _{Calcd for C 31 H 28 N 4} O 2 · 0.25H 2 O: C, 75.51; H, 5.83; N, 11.36. Found: C, 75.65; H, 5.51; N, 11.41.

[Example 8]
5-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -6- (3-hydroxyphenyl) [1] benzofuro [2,3-b] pyridine-8-carbonitrile (# 8)
6- [3- (Benzyloxy) phenyl] -5-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] [1] benzofuro [2,3-b] pyridine-8-carbonitrile (# 7) Acetic acid (7 μl) was added to a suspension of tetrahydrofuran (1 ml) in (20 mg, 40.9 μmol) and 10% palladium carbon catalyst (4 mg), and the mixture was stirred for 6.5 days in a hydrogen atmosphere. The reaction system was purged with nitrogen, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. Next, the obtained residue was dissolved in chloroform, the organic layer was washed with 1N aqueous sodium hydroxide solution, and the aqueous layer was extracted with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 2 mg of the crude title compound was obtained as a white solid from a dichloromethane-methanol (20: 1, v / v) eluate. Similarly, 6- [3- (benzyloxy) phenyl] -5-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] [1] benzofuro [2,3-b] pyridine- From 137 mg (280 μmol) of 8-carbonitrile (# 7), 7 mg of the crude title compound was obtained as a pale yellow solid. These were combined, subjected to silica gel column chromatography again, and 5 mg of the title compound was obtained as a white solid from the eluate of dichloromethane-methanol (10: 1, v / v).

MS (ESI) m / z: 399 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 1.82-1.96 (1H, m), 2.10-2.19 (1H, m), 2.30 (6H, s), 2.86-2 .97 (1H, m), 3.12-3.28 (3H, m), 3.43-3.50 (1H, m), 6.84-6.90 (3H, m), 7.31 −7.36 (1H, m), 7.44 (1H, dd, J = 7.8, 4.9 Hz), 7.61 (1H, s), 8.09 (1H, dd, J = 7. 8, 1.7 Hz), 8.52 (1H, dd, J = 4.9, 1.7 Hz).

[Reference Example 26]
Methyl 6-fluoro-4-hydroxy-3'-nitrobiphenyl-3-carboxylate (I-26)
Under a nitrogen atmosphere, methyl 5-bromo-4-fluoro-2-hydroxybenzoate (I-1) (5.23 g, 21.0 mmol), 3-nitrophenylboronic acid (5.26 g, 31.5 mmol), phosphoric acid A suspension of tripotassium (8.92 g, 42.0 mmol) and tetrakis (triphenylphosphine) palladium (0) (1.21 g, 1.05 mmol) in 1,4-dioxane (105 ml) was heated to reflux for 70 minutes. . After cooling, the reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 3.34 g (55%) of the title compound was obtained as a pale yellow solid from a fraction eluted with n-hexane-ethyl acetate (8: 1, v / v).
MS (ESI) m / z: 292 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 4.00 (3H, s), 6.83 (1H, d, J = 11.7 Hz), 7.62 (1H, t, J = 8.1 Hz), 7 .85 (1H, d, J = 7.6 Hz), 8.00 (1H, d, J = 8.8 Hz), 8.23 (1H, d, J = 8.1 Hz), 8.37 (1H, s), 11.06 (1H, s).
IR (ATR): 1668, 1604, 1527, 1446, 1342, 1284, 1254, 1221, 1149, 1105 cm ⁻¹ .

[Reference Example 27]
Methyl 6-fluoro-4-hydroxy-5-iodo-3′-nitrobiphenyl-3-carboxylate (I-27)
To a mixed solution of methyl 6-fluoro-4-hydroxy-3′-nitrobiphenyl-3-carboxylate (I-26) (3.34 g, 11.5 mmol) in methanol-dichloromethane (29 ml-115 ml), benzyltrimethylammonium dichloro Iodine salt (4.79 g, 13.8 mmol) and sodium hydrogen carbonate (6.28 g, 74.8 mmol) were added under ice cooling, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 4.32 g (90%) of the title compound was obtained as a yellow solid from a fraction eluted with n-hexane-chloroform (1: 1, v / v).
MS (EI) m / z: 418 (M ^<+> ).
¹ H-NMR (CDCl ₃ ) δ: 4.03 (3H, s), 7.61-7.66 (1H, m), 7.82-7.86 (1H, m), 8.02 (1H , D, J = 8.8 Hz), 8.23-8.27 (1H, m), 8.35-8.38 (1H, m), 11.98-12.00 (1H, m).
IR (ATR): 3076, 1674, 1529, 1439, 1342, 1246, 1205 cm ⁻¹ .

[Reference Example 28]
Methyl 6-fluoro-5-iodo-4-methoxy-3'-nitrobiphenyl-3-carboxylate (I-28)
Methyl 6-fluoro-4-hydroxy-5-iodo-3′-nitrobiphenyl-3-carboxylate (I-27) (4.32 g, 10.4 mmol), potassium carbonate (1.72 g, 12.5 mmol) and A suspension of dimethyl sulfate (1.08 ml, 11.4 mmol) in acetonitrile (100 ml) was stirred at 60 ° C. for 4 hours. After cooling, the reaction mixture was diluted with diethyl ether and washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Since the presence of unreacted raw materials was confirmed by ¹ H-NMR and LC-MS of the obtained solid, potassium carbonate (860 mg), dimethyl sulfate (540 μl) and acetonitrile (100 ml) were used again at 60 ° C. at 23 ° C. Stir for 5 hours. After cooling, the same post-treatment was performed, and the obtained solid was suspended and washed with diisopropyl ether to obtain 3.30 g (74%) of the title compound as a pale yellow solid.
MS (ESI) m / z: 432 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 3.97 (3H, s), 3.98 (3H, s), 7.66 (1H, t, J = 7.8 Hz), 7.86 (1H, d , J = 7.8 Hz), 8.01 (1H, d, J = 8.8 Hz), 8.28 (1H, d, J = 8.3 Hz), 8.39 (1H, s).
IR (ATR): 1732, 1525, 1348, 1238, 1200 cm ⁻¹ .

[Reference Example 29]
6-Fluoro-5-iodo-4-methoxy-3'-nitrobiphenyl-3-carboxylic acid (I-29)
To a solution of methyl 6-fluoro-5-iodo-4-methoxy-3′-nitrobiphenyl-3-carboxylate (I-28) (2.80 g, 6.49 mmol) in methanol (32 ml) was added 1N sodium hydroxide. Aqueous solution (7.14 ml, 7.14 mmol) was added and heated to reflux for 2.5 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with water. The aqueous layer was washed with n-hexane, acidified with 1N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The combined organic layers were then dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2.56 g (95%) of the title compound as a pale yellow solid.
MS (ESI) m / z: 418 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 4.08 (3H, s), 7.67 (1H, t, J = 8.1 Hz), 7.84-7.88 (1H, m), 8.24 (1H, d, J = 8.8 Hz), 8.28-8.32 (1H, m), 8.41 (1H, s).
IR (ATR): 1678, 1527, 1458, 1348, 1292, 1257 cm ⁻¹ .

[Reference Example 30]
6-Fluoro-5-iodo-4-methoxy-3'-nitrobiphenyl-3-carboxamide (I-30)
To a solution of 6-fluoro-5-iodo-4-methoxy-3′-nitrobiphenyl-3-carboxylic acid (I-29) (2.56 g, 6.14 mmol) in N, N-dimethylformamide (61 ml) at room temperature. 1-hydroxybenzotriazole (996 mg, 7.37 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1.41 g, 7.37 mmol) and 28% aqueous ammonia (1. 12 ml, 18.4 mmol) was added and stirred for 15.5 hours. After the reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in chloroform, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate, 1N aqueous hydrochloric acid, water and saturated brine. Next, the aqueous layer was extracted with chloroform, and the combined organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was suspended and washed in diisopropyl ether to give 2.26 g (89%) of the title compound as a pale yellow solid.
MS (ESI) m / z: 417 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 3.97 (3H, s), 5.87 (1H, brs), 7.55 (1H, brs), 7.63-7.67 (1H, m), 7.85-7.89 (1H, m), 8.26-8.29 (2H, m), 8.41-8.43 (1H, m).
IR (ATR): 3446, 3298, 1682, 1641, 1583, 1533, 1456, 1406, 1352 cm ⁻¹ .

[Reference Example 31]
6-Fluoro-5-iodo-4-methoxy-3'-nitrobiphenyl-3-carbonitrile (I-31)
Under a nitrogen atmosphere, 6-fluoro-5-iodo-4-methoxy-3′-nitrobiphenyl-3-carboxamide (I-30) (2.26 g, 5.43 mmol) and 4- (dimethylamino) pyridine (33 mg, To a solution of 272 μmol) in pyridine (22 ml), trifluoromethanesulfonic anhydride (1.37 ml, 8.15 mmol) was added dropwise at 0 ° C., pyridine (10 ml) was added, and the mixture was stirred at room temperature for 17.5 hours. . The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the obtained residue, and the organic layer was washed with 1N aqueous hydrochloric acid solution, water and saturated brine. Subsequently, insoluble matters in the organic layer were collected by filtration, and the obtained solid was suspended and washed in diisopropyl ether to obtain 1.68 g (78%) of the title compound as a white solid.
MS (EI) m / z: 398 (M ^<+> ).
¹ H-NMR (CDCl ₃ ) δ: 4.20 (3H, s), 7.66-7.72 (2H, m), 7.79-7.82 (1H, m), 8.28-8 .33 (1H, m), 8.34-8.38 (1H, m).
IR (ATR): 2227, 1525, 1466, 1414, 1348, 1240, 1147 cm ⁻¹ .

[Reference Example 32]
3′-Acetamide-6-fluoro-5-iodo-4-methoxy-3-carbonitrile (I-32)
6-Fluoro-5-iodo-4-methoxy-3′-nitrobiphenyl-3-carbonitrile (I-31) (1.07 g, 2.69 mmol) and iron powder (450 mg, 8.06 mmol) in acetic acid (27 ml) ) The suspension was heated to reflux for 20 hours. After cooling, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. Next, a saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 730 mg (66%) of the title compound was obtained as a white solid from a fraction eluted with n-hexane-ethyl acetate (1: 1, v / v).
MS (EI) m / z: 411 (M ^<+> ).
¹ H-NMR (CDCl ₃ ) δ: 2.20 (3H, s), 4.15 (3H, s), 7.19 (1H, d, J = 7.6 Hz), 7.40 (2H, t , J = 7.8 Hz), 7.51 (1H, d, J = 7.8 Hz), 7.65 (1H, d, J = 8.1 Hz), 7.70 (1H, s).
IR (ATR): 3356, 3315, 3282, 2229, 1668, 1593, 1552, 1466, 1404, 1367, 1250 cm ⁻¹ .

[Reference Example 33]
3′-Amino-6-fluoro-5-iodo-4-methoxybiphenyl-3-carbonitrile (I-33)
Concentrated hydrochloric acid (3 ml) was added to a solution of 3′-acetamide-6-fluoro-5-iodo-4-methoxy-3-carbonitrile (I-32) (455 mg, 1.11 mmol) in ethanol (10 ml), and the mixture was heated to 70 ° C. For 3.5 hours. After cooling, the precipitated solid was collected by filtration, and this solid was washed with ethanol. Next, this solid was suspended in water, 1N aqueous sodium hydroxide solution was added, and the aqueous layer was extracted with a chloroform-methanol mixed solvent. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 264 mg (65%) of the title compound as a white solid.
MS (EI) m / z: 369 (M ^<+> ).
¹ H-NMR (CDCl ₃ ) δ: 3.78 (2H, brs), 4.14 (3H, s), 6.71-6.77 (2H, m), 6.80-6.84 (1H M), 7.23 (1H, d, J = 7.6 Hz), 7.65 (1H, d, J = 8.1 Hz).
IR (ATR): 3421, 3332, 2229, 1597, 1589, 1468, 1419, 1394, 1269 cm ⁻¹ .

[Reference Example 34]
3′-Amino-6-fluoro-5- (2-fluoropyridin-3-yl) -4-methoxybiphenyl-3-carbonitrile (I-34)
Under a nitrogen atmosphere, 3′-amino-6-fluoro-5-iodo-4-methoxybiphenyl-3-carbonitrile (I-33) (346 mg, 940 μmol), 2-fluoro-3- (4, 4, 5, 5-tetramethyl [1,3,2] dioxaborolan-2-yl) pyridine (252 mg, 1.13 mmol), cesium carbonate (613 mg, 1.88 mmol) and tetrakis (triphenylphosphine) palladium (0) (54 mg, 47 μmol) ) In toluene (10 ml) was heated to reflux for 24 hours. After cooling, the reaction solution was filtered, and the filtrate was washed with water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 141 mg (45%) of the title compound was obtained as a yellow oil from a fraction eluted with n-hexane-ethyl acetate (2: 1, v / v).
MS (ESI) m / z: 338 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 3.81-4.05 (2H, m), 3.93 (3H, s), 6.72-6.77 (1H, m), 6.81 (1H , Q, J = 1.8 Hz), 6.85-6.89 (1H, m), 7.22-7.27 (1H, m), 7.31-7.35 (1H, m), 7 .74 (1H, d, J = 8.1 Hz), 7.79-7.85 (1H, m), 8.32-8.35 (1H, m).
IR (ATR): 3465, 3367, 2231, 1604, 1570, 1473, 1419, 1398, 1250 cm ⁻¹ .

[Example 9]
5-[(3S) -3- (Dimethylamino) pyrrolidin-1-yl] -6- (3-aminophenyl) [1] benzofuro [2,3-b] pyridine-8-carbonitrile (# 9)
Under a nitrogen atmosphere, 3′-amino-6-fluoro-5- (2-fluoropyridin-3-yl) -4-methoxybiphenyl-3-carbonitrile (I-34) (137 mg, 406 μmol) and triethylamine (137 μl, 1.22 mmol) of dimethyl sulfoxide (4 ml) was stirred at 130 ° C. for 19.5 hours, (3S) -3- (dimethylamino) pyrrolidine (103 μl, 812 μmol) was added at the same temperature, Stir for 6 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform. Next, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, and then the aqueous layer was extracted with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give the crude title compound from the eluate of dichloromethane-methanol (20: 1, v / v), and the suspension was washed with diisopropyl ether to give 46 mg (29%) of the title compound. ) Was obtained as a pale pale yellow solid.

MS (ESI) m / z: 398 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 1.81-1.91 (1H, m), 2.09-2.19 (1H, m), 2.22 (6H, s), 2.72-2 .81 (1H, m), 3.06-3.14 (1H, m), 3.18-3.26 (2H, m), 3.28-3.35 (1H, m), 3.80 (2H, brs), 6.61-6.63 (1H, m), 6.65-6.68 (1H, m), 6.72-6.75 (1H, m), 7.22 (1H , T, J = 7.8 Hz), 7.43 (1H, dd, J = 7.8, 4.9 Hz), 7.57 (1H, s), 8.14 (1H, dd, J = 7. 8, 1.7 Hz), 8.50 (1H, dd, J = 4.9, 1.7 Hz).
IR (ATR): 2224, 1599, 1469, 1446, 1390, 1363, 1209, 1159 cm ⁻¹ .
Anal. _{Calcd for C 24 H 23 N 5} O · 0.25H 2 O: C, 71.71; H, 5.89; N, 17.42. Found: C, 71.65; H, 5.78; N, 17.09.

[Reference Example 35]
Methyl 5-bromo-4-fluoro-2-hydroxy-3-iodobenzoate (I-35)
To a mixed solution of methyl 5-bromo-4-fluoro-2-hydroxybenzoate (I-1) (2.79 g, 11.2 mmol) in methanol-dichloromethane (56 ml-220 ml), benzyltrimethylammonium dichloroiodate (4.68 g) was added. , 13.4 mmol) and sodium hydrogen carbonate (6.12 g, 72.8 mmol) were added at room temperature and stirred for 19 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 3.69 g (88%) of the title compound was obtained as a white solid from a fraction eluted with n-hexane-ethyl acetate (8: 1, v / v).
MS (EI) m / z: 374, 376 (M ^<+> ).
¹ H-NMR (CDCl ₃ ) δ: 3.99 (3H, s), 8.10 (1H, d, J = 7.8 Hz), 11.85 (1H, s).
IR (ATR): 1668, 1591, 1319, 1236, 1213, 1122 cm ⁻¹ .

[Reference Example 36]
Methyl 5-bromo-4-fluoro-3-iodo-2-methoxybenzoate (I-36)
Methyl 5-bromo-4-fluoro-2-hydroxy-3-iodobenzoate (I-35) (2.19 g, 5.84 mmol), potassium carbonate (969 mg, 7.01 mmol) and dimethyl sulfate (610 μl, 6.43 mmol) ) In acetonitrile (60 ml) was stirred at 60 ° C. for 1.5 hours. After cooling, the reaction mixture was diluted with diethyl ether and washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 2.14 g (94%) of the title compound was obtained as a white solid from a fraction eluted with n-hexane-ethyl acetate (9: 1, v / v).
MS (ESI) m / z: 389, 391 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 3.91 (3H, s), 3.93 (3H, s), 8.10 (1H, d, J = 8.1 Hz).
IR (ATR): 1728, 1458, 1429, 1373, 1282, 1238, 1186, 1109 cm ⁻¹ .

[Reference Example 37]
5-Bromo-4-fluoro-3-iodo-2-methoxybenzoic acid (I-37)
To a solution of methyl 5-bromo-4-fluoro-3-iodo-2-methoxybenzoate (I-36) (2.14 g, 5.50 mmol) in methanol (21 ml) was added 1N aqueous sodium hydroxide solution (6.05 ml (6 .05 mmol) was added and heated to reflux for 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with water. The aqueous layer was washed with n-hexane, acidified with 1N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The combined organic layers were then dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 2.04 g (99%) of the title compound as a white solid.
MS (EI) m / z: 374, 376 (M ^<+> ).
¹ H-NMR (CDCl ₃ ) δ: 4.00 (3H, s), 8.31 (1H, d, J = 7.8 Hz).
IR (ATR): 1668, 1574, 1452, 1419, 1373, 1292, 1248, 1221 cm ⁻¹ .

[Reference Example 38]
5-Bromo-4-fluoro-3-iodo-2-methoxybenzoic acid amide (I-38)
To a solution of 5-bromo-4-fluoro-3-iodo-2-methoxybenzoic acid (I-37) (2.04 g, 5.44 mmol) in N, N-dimethylformamide (55 ml) at room temperature was added 1-hydroxy. Benzotriazole (882 mg, 6.53 mmol), 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1.25 g, 6.53 mmol) and 28% aqueous ammonia (993 μl, 16.3 mmol). The mixture was further stirred for 15.5 hours. After the reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in chloroform, and this organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, a 1N aqueous hydrochloric acid solution and a saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was suspended and washed with diethyl ether to give 1.59 g (78%) of the title compound as a white solid.
MS (ESI) m / z: 374, 376 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 3.90 (3H, s), 5.85 (1H, brs), 7.47 (1H, brs), 8.35 (1H, d, J = 8.1 Hz) ).
IR (ATR): 3411, 3186, 1645, 1616, 1576, 1450, 1404, 1356, 1211, 1122, 1043 cm ⁻¹ .

[Reference Example 39]
5-Bromo-4-fluoro-3-iodo-2-methoxybenzonitrile (I-39)
Under nitrogen atmosphere, 5-bromo-4-fluoro-3-iodo-2-methoxybenzoic acid amide (I-38) (1.59 g, 4.25 mmol) and 4- (dimethylamino) pyridine (26 mg, 213 μmol). To a pyridine (17 ml) solution, trifluoromethanesulfonic anhydride (1.50 ml, 5.59 mmol) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 20.5 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in ethyl acetate, and the organic layer was washed with 1N aqueous hydrochloric acid solution, water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was suspended and washed with diethyl ether to give 660 mg of the title compound as a milky white solid. The residue obtained by concentrating the filtrate was suspended and washed with diisopropyl ether to obtain 539 mg and 206 mg of the title compound, giving a total of 1.41 g (93%).
MS (EI) m / z: 355, 357 (M ^<+> ).
¹ H-NMR (CDCl ₃ ) δ: 4.11 (3H, s), 7.65 (1H, d, J = 7.3 Hz).
IR (ATR): 2231, 1460, 1431, 1381, 1227, 1153, 1051 cm ⁻¹ .

[Reference Example 40]
5-Bromo-4-fluoro-3- (2-fluoropyridin-3-yl) -2-methoxybenzonitrile (I-40)
Under a nitrogen atmosphere, 5-bromo-4-fluoro-3-iodo-2-methoxybenzonitrile (I-39) (646 mg, 1.81 mmol), 2-fluoro-3- (4,4,5,5-tetra To a solution of methyl [1,3,2] dioxaborolan-2-yl) pyridine (486 mg, 2.18 mmol) and tetrakis (triphenylphosphine) palladium (0) (105 mg, 91 μmol) in 1,2-dimethoxyethane (18 ml). Then, 1.5M aqueous sodium carbonate solution was added, and the mixture was heated to reflux for 23 hours. After cooling, the reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain the crude title compound from the eluate of n-hexane-ethyl acetate (4: 1, v / v), and suspended and washed with diisopropyl ether. Filtered off. After the filtrate was concentrated, the obtained residue was subjected to silica gel column chromatography, and 53 mg (9%) of the title compound was obtained as a yellow oil from a toluene-acetone (50: 1, v / v) eluate.
MS (ESI) m / z: 325, 327 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 3.91 (3H, s), 7.32-7.36 (1H, m), 7.75-7.80 (1H, m), 7.87 (1H , D, J = 7.3 Hz), 8.34-8.37 (1H, m).

[Reference Example 41]
6-Bromo-5-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-41)
Under a nitrogen atmosphere, 5-bromo-4-fluoro-3- (2-fluoropyridin-3-yl) -2-methoxybenzonitrile (I-40) (112 mg, 344 μmol) and triethylamine (144 μl, 1.03 mmol) The dimethyl sulfoxide (3 ml) solution was stirred at 130 ° C. for 18 hours, and (3S) -3- (dimethylamino) pyrrolidine (87 μl, 688 μmol) was added at the same temperature, followed by stirring for 80 minutes. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform. Next, the organic layer was washed with water, and then the aqueous layer was extracted with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 37 mg (28%) of the title compound was obtained as a pale yellow solid from an eluate of dichloromethane-methanol (20: 1, v / v).
MS (ESI) m / z: 385, 387 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.09-2.21 (1H, m), 2.34-2.38 (1H, m), 2.37 (6H, s), 3.01-3 .10 (1H, m), 3.51-3.57 (1H, m), 3.59-3.73 (3H, m), 7.45 (1H, dd, J = 7.8,4. 9 Hz), 7.93 (1 H, s), 8.32 (1 H, dd, J = 7.8, 1.7 Hz), 8.53 (1 H, dd, J = 4.9, 1.7 Hz).

[Example 10]
5-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -6- (pyridin-3-yl) [1] benzofuro [2,3-b] pyridine-8-carbonitrile (# 10)
Under a nitrogen atmosphere, 6-bromo-5-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-41) ( 43 mg, 112 μmol)), 1,4-pyridine-3-boronic acid (27 mg, 223 μmol), tripotassium phosphate (47 mg, 223 μmol) and tetrakis (triphenylphosphine) palladium (0) (13 mg, 11.2 μmol). The dioxane (1 ml) suspension was heated to reflux for 19 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform. Next, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, and then the aqueous layer was extracted with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 4 mg (9%) of the title compound was obtained as a light brown solid from a dichloromethane-methanol (20: 1, v / v) eluate.

MS (ESI) m / z: 384 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 1.80-1.96 (1H, m), 2.12-2.22 (1H, m), 2.21 (6H, s), 2.71-2 .80 (1H, m), 3.07-3.26 (4H, m), 7.42-7.49 (2H, m), 7.57 (1H, s), 7.66-7.69 (1H, m), 8.18-8.22 (1H, m), 8.53 (1H, dd, J = 4.9, 1.7 Hz), 8.62-8.63 (1H, m) , 8.69 (1H, dd, J = 4.9, 1.7 Hz).

[Reference Example 42]
2,4-Dihydroxy-6-methylbenzaldehyde (I-42)
J. et al. Org. Chem. , 60 , 5717 (1995).
Under nitrogen atmosphere, N, N-dimethylformamide (450 ml) was ice-cooled, phosphorus oxychloride (90 ml) was added dropwise while adjusting the temperature to 10 ° C. or lower, and the mixture was vigorously stirred for 30 minutes. A solution of 3,5-dihydroxytoluene (100 g, 805.5 mmol) in N, N-dimethylformamide (200 ml) was added dropwise at 10 ° C. or lower, and the mixture was stirred at room temperature for 1 hour. The reaction solution was ice-cooled, adjusted to pH = 9 with a 10% aqueous sodium hydroxide solution, and heated and stirred for 10 minutes to make the suspension a uniform phase. The mixture was ice-cooled again, acidified to pH = 3 with a 10% aqueous hydrochloric acid solution, and the precipitated solid was collected by filtration while washing with water. The obtained solid was dried under reduced pressure to obtain 81.69 g (67%) of the title compound as a yellow solid.
MS (ESI) m / z: 153 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.45 (3H, s), 3.81 (1H, s), 5.86 (1H, s), 6.32 (1H, s), 6.40 ( 1H, s).

[Reference Example 43]
2-Cyano-5-methoxy-3-methylphenyl acetate (I-43)
2,4-Dihydroxy-6-methylbenzaldehyde (I-42) (23.4 g, 153.85 mmol) was dissolved in acetonitrile (420 ml) and methanol (46 ml), and diisopropylethylamine (34.5 ml, 200 mmol) was added. . Under ice cooling, trimethylsilyldiazomethane (2M n-hexane solution) (100 ml, 200 mmol) was added dropwise and stirred vigorously. Since the reaction was not completed, trimethylsilyldiazomethane (2M n-hexane solution) (15.4 ml, 40 mmol) and diisopropylethylamine (5.3 ml, 40 mmol) were added dropwise and stirred for 2.5 hours. The solvent was concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography and eluted with a mixed solvent of n-hexane-ethyl acetate (4: 1, v / v) to give 2-hydroxy-4-methoxy- 16.56 g (99.66 mmol) of 6-methylbenzaldehyde was obtained as a yellow solid. This was dissolved in ethanol (170 ml), hydroxylamine hydrochloride (7.27 g, 104.64 mmol) was added, and the mixture was heated to reflux. The mixture was allowed to cool to room temperature, and the precipitated yellow solid was collected by filtration with washing with ethanol to obtain an oxime compound (12.65 g, 58.12 mmol). The filtrate was concentrated under reduced pressure and fractionated with ethyl acetate and aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 6.62 g (36.53 mmol) of oxime as a crude product as a brown oily substance (19.27 g in total). The oxime compound (15.58 g, 71.58 mmol) was dissolved in acetic anhydride (78 ml) and stirred at 140 ° C. for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and azeotroped with toluene. The obtained residue was recrystallized and purified with diisopropyl ether to obtain a yellowish white solid. Ethyl acetate was added to the filtrate, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized and purified with diisopropyl ether and combined with the yellowish white solid to obtain 12.43 g of the title compound as a pale yellow solid.
MS (ESI) m / z: 206 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.38 (3H, s), 2.51 (3H, s), 3.83 (4H, s), 6.60 (1H, d, J = 2.0 Hz) ), 6.69 (1H, dd, J = 0.6, 2.3 Hz).

[Reference Example 44]
2-Hydroxy-4-methoxy-6-methylbenzonitrile (I-44)
2-Cyano-5-methoxy-3-methylphenylacetate (I-43) (12.43 g, 60.57 mmol) was dissolved in a mixed solution of tetrahydrofuran (60 ml) and methanol (60 ml), and 1N aqueous potassium carbonate solution ( 66.7 ml, 66.63 mmol) was added, and the mixture was stirred at room temperature for 13 hours. After completion of the reaction, water was added, the solution was acidified to pH = 1 with a 1N hydrochloric acid aqueous solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the resulting residue was recrystallized with a mixed solvent of n-hexane-ethyl acetate to obtain 8.25 g (83%) of the title compound as a yellow solid.
MS (ESI) m / z: 164 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.34 (3H, s), 3.75 (3H, s), 6.33 (1H, d, J = 2.0 Hz), 6.44 (1H, d , J = 1.0 Hz).

[Reference Example 45]
3-Bromo-6-hydroxy-4-methoxy-2-methylbenzonitrile (I-45)
2-hydroxy-4-methoxy-6-methylbenzonitrile (I-44) (15.26 g, 93.52 mmol) was dissolved in a mixed solution of chloroform (75 ml) and methanol (75 ml), and bromine ( A chloroform solution (15 ml) of 2.83 ml, 93.52 mmol) was added dropwise over 30 minutes, and the mixture was stirred at 0 ° C. for 30 minutes. A saturated aqueous sodium thiosulfate solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was recrystallized from a mixed solvent of diisopropyl ether-ethyl acetate-chloroform to obtain 17.54 g (77%) of the title compound as a yellow solid.
MS (ESI) m / z: 240, 242 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 2.46 (3H, s), 3.85 (3H, s), 6.52 (1H, s).

[Reference Example 46]
6-methoxy-4- (methoxymethoxy) -2-methylbiphenyl-3-carbonitrile (I-46)
Under a nitrogen atmosphere, 3-bromo-6-hydroxy-4-methoxy-2-methylbenzonitrile (I-45) (15.0 g, 61.97 mmol) was dissolved in N, N-dimethylformamide (125 ml) at room temperature. Phenylboronic acid (9.07 g, 74.36 mmol), cesium carbonate (44.4 g, 136.33 mmol) and tetrakis (triphenylphosphine) palladium (0) (2.15 g, 1.86 mmol) were added. After stirring at 80 ° C. for 20 hours, the mixture was cooled to room temperature. The insoluble material was removed by filtration with washing with ethyl acetate, and the filtrate was fractionated with ethyl acetate and 1N aqueous hydrochloric acid. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the resulting residue was recrystallized with a mixed solvent of diisopropyl ether-ethyl acetate-toluene to give 4-hydroxy-6-methoxy-2-methylbiphenyl-3-carbonitrile and unreacted raw materials ( I-45) was obtained as a white solid, 11.24 g (mixing ratio about 2: 1). The obtained crude product was dissolved in N, N-dimethylformamide (79 ml), and potassium carbonate (4.61 g, 33.39 mmol) and chloromethyl methyl ether (2.97 ml, 39.45 mmol) were added under ice cooling. And stirred at room temperature for 18 hours. The reaction solution was fractionated with diethyl ether and water. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, eluted with a mixed solvent of n-hexane-ethyl acetate (4: 1, v / v), and a mixture of the title compound and I-45. 7.35 g (mixing ratio about 2: 1) was obtained as a white solid. This was dissolved in N, N-dimethylformamide (70 ml), phenylboronic acid (1.88 g, 15.41 mmol), cesium carbonate (5.02 g, 15.41 mmol), and tetrakis (triphenylphosphine) at room temperature. Palladium (0) (445 mg, 0.39 mmol) was added. After stirring at 80 ° C. for 11 hours, the mixture was cooled to room temperature. The insoluble material was removed by filtration with washing with ethyl acetate, and the filtrate was fractionated with ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, eluting with a mixed solvent of n-hexane-ethyl acetate (3: 1, v / v) to give 6.86 g (39%) of the title compound. ) Was obtained as a pale yellow oil.
MS (ESI) m / z: 284 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.21 (3H, s), 3.57 (3H, s), 3.74 (3H, s), 5.33 (2H, s), 6.69 ( 1H, s), 7.13 (2H, dd, J = 1.5, 7.3 Hz), 7.34-7.44 (3H, m).

[Reference Example 47]
4-hydroxy-6-methoxy-2-methylbiphenyl-3-carbonitrile (I-47)
6-Methoxy-4- (methoxymethoxy) -2-methylbiphenyl-3-carbonitrile (I-46) (4.93 g, 17.38 mmol) was dissolved in methanol (50 ml) and 2 drops of concentrated hydrochloric acid were added. The mixture was stirred at 60 ° C. for 20 hours. After allowing to cool, the solvent was concentrated under reduced pressure, and the resulting residue was recrystallized with a mixed solvent of n-hexane-ethyl acetate to obtain 3.47 g (84%) of the title compound as a white solid.
MS (ESI) m / z: 240 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.20 (3H, s), 3.72 (3H, s), 6.44 (1H, s), 7.12 (1H, s), 7.14 ( 1H, d, J = 1.5 Hz), 7.36-7.44 (3H, m).

[Reference Example 48]
4-[(3-Iodopyridin-2-yl) oxy] -6-methoxy-2-methylbiphenyl-3-carbonitrile (I-48)
Under a nitrogen atmosphere, 4-hydroxy-6-methoxy-2-methylbiphenyl-3-carbonitrile (I-47) 500 mg (2.09 mmol), 2-fluoro-3-iodopyridine (559 mg, 2.51 mmol) and carbonic acid Cesium (817 mg, 2.51 mmol) was dissolved in dimethyl sulfoxide (10 ml) and stirred at 80 ° C. for 19 hours. After cooling to room temperature, diethyl ether and water were added for fractionation, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was recrystallized from a mixed solvent of n-hexane-ethyl acetate-diisopropyl ether to obtain 428 mg (46%) of the title compound as a yellowish white solid.
MS (ESI) m / z: 443 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.26 (3H, s), 3.73 (3H, s), 6.73 (1H, s), 6.85 (1H, dd, J = 4.8) , 7.4 Hz), 7.19 (1H, dd, J = 1.5, 6.8 Hz), 7.36-7.47 (3H, m), 8.14-8.22 (2H, m) .

[Reference Example 49]
5-hydroxy-7-methyl-6-phenyl [1] benzfuro [2,3-b] pyridine-8-carbonitrile (I-49)
Under nitrogen atmosphere 4-[(3-iodopyridin-2-yl) oxy] -6-methoxy-2-methylbiphenyl-3-carbonitrile (I-48) (60 mg, 0.14 mmol) and sodium acetate (33 0.5 mg, 0.41 mmol) was dissolved in dimethylacetamide (24 ml), palladium acetate (4.6 mg, 0.02 mmol) was added, and the mixture was stirred at 130 ° C. for 1.5 hours. After allowing to cool to room temperature, diethyl ether was added, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, the solvent was concentrated under reduced pressure, and the obtained residue was recrystallized from a mixed solvent of n-hexane-ethyl acetate-chloroform-methanol to obtain 38 mg (89%) of the title compound. Obtained as a pale yellow solid.
MS (ESI) m / z: 301 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.41 (3H, s), 6.01 (1H, br s), 7.32-7.34 (2H, m), 7.38 (1H, dd, J = 4.9, 7.3 Hz), 7.53-7.64 (3H, m), 8.35 (1H, dd, J = 1.7, 7.6 Hz), 8.46 (1H, dd) , J = 1.7, 4.9 Hz).

[Reference Example 50]
8-cyano-7-methyl-6-phenyl [1] benzofuro [2,3-b] pyridin-5-yl trifluoromethanesulfonate (I-50)
Under a nitrogen atmosphere 5-hydroxy-7-methyl-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-49) (331 mg, 1.10 mmol) and 4- (dimethylamino) ) Pyridine (6.7 mg, 0.06 mmol) was dissolved in pyridine (6 ml), trifluoromethanesulfonic anhydride (558 μl, 3.30 mmol) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. Ice water was added to the reaction solution, and pyridine was distilled off under reduced pressure. A 1N aqueous hydrochloric acid solution was added, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from a mixed solvent of diisopropyl ether-ethyl acetate-n-hexane to obtain 471 mg (98%) of the title compound as a white solid.
MS (ESI) m / z: 433 (M + 1) ^<+> .

[Example 11]
5-[(3S) -3- (dimethylamino) -1-pyrrolidinyl] -7-methyl-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (# 11)

  Cesium carbonate (476.2 mg, 1.46 mmol) and (3S) -3- (dimethylamino) pyrrolidine (159 μl, 1.25 mmol) were dissolved in toluene (3 ml) under a nitrogen atmosphere, and palladium acetate (4.7 mg, 0.02 mmol) and 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (14.3 mg, 0.02 mmol) were added, and the mixture was stirred at 80 ° C. for 10 minutes. Toluene solution (1 ml) of 8-cyano-7-methyl-6-phenyl [1] benzofuro [2,3-b] pyridin-5-yl trifluoromethanesulfonate (I-50) (452 mg, 1.04 mmol) was slowly added. And added dropwise over 20 minutes and stirred at 80 ° C. for 16 hours. The reaction solution was allowed to cool, diluted with chloroform, and the insoluble material was removed by filtration. The obtained filtrate was concentrated under reduced pressure, and fractionated with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to silica gel column chromatography, eluting with a mixed solvent of n-hexane-ethyl acetate (10: 1, v / v, containing 1% triethylamine) to give the title compound 8.6 mg (2%) was obtained as a light brown solid.

mp: 206-208 ° C
MS (ESI) m / z: 397 (M + 1) ⁺ .
¹ H-NMR (DMSO-d ₆ ) δ: 1.66-1.76 (1H, m), 2.02-2.10 (1H, m), 2.14 (6H, s), 2.33 (3H, s), 2.55-2.63 (1H, m), 2.74 (1H, t, J = 8.4 Hz), 2.98-3.10 (3H, m), 7.15 -7.23 (2H, m), 7.39-7.50 (4H, m), 8.10 (1H, dd, J = 1.7, 7.8 Hz), 8.47 (1H, dd, J = 1.6, 5.0 Hz).
IR (ATR): 2218, 1460, 1390 cm ⁻¹ .
Anal. _{Calcd for C 25 H 24 N 4} O · 0.5H 2 O: C, 74.05; H, 6.20; N, 13.82. Found: C, 73.65; H, 5.87; N, 13.38.

[Example 12]
5-[(3S) -3- (dimethylamino) -1-pyrrolidinyl] -7-methyl-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carboxamide (# 12)
Under nitrogen atmosphere, 5-[(3S) -3- (dimethylamino) -1-pyrrolidinyl] -7-methyl-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile hydrochloride ( # 12) (20 mg, 0.04 mmol) was dissolved in ethanol (0.2 ml), 1N aqueous sodium hydroxide solution (100 μl, 0.10 mmol) was added, and the mixture was heated to reflux for 47 hours. Since the reaction was not completed, 25% aqueous sodium hydroxide solution (200 μl) was added, and the mixture was further heated to reflux for 24 hours. After cooling to room temperature, chloroform was added, neutralized with 1N aqueous hydrochloric acid solution, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was recrystallized from a mixed solvent of ethyl acetate-diisopropyl ether to obtain 10 mg (58%) of the title compound as a white solid.

MS (FAB) m / z: 415 (M + 1) ^<+> .
HRMS (FAB) m / z: 415.2121 (Calcd for C 25 H 26 N 4 O 2 415.2134).
¹ H-NMR (DMSO-d ₆ ) δ: 1.70 (1H, br s), 2.04 (1H, br s), 2.14 (6H, s), 2.31 (3H, s), 2.56 (1H, br s), 2.72 (1H, br s), 3.01-3.10 (3H, m), 5.93 (1H, br s), 6.55 (1H, br s), 7.20 (1H, dd, J = 8.1, 12.9 Hz), 7.37-7.48 (4H, m), 8.15 (1H, dd, J = 1.7, 7) .8 Hz), 8.41 (1H, dd, J = 1.7, 5.1 Hz).
IR (ATR): 2835, 1678, 1385 cm ⁻¹ .

[Reference Example 51]
tert-Butyl [3- (8-cyano-7-methyl-6-phenyl [1] benzofuro [2,3-b] pyridin-5-yl) cyanopent-2-en-1-yl] carbamate (I-51 )
8-cyano-7-methyl-6-phenyl [1] benzofuro [2,3-b] pyridin-5-yl trifluoromethanesulfonate (I-50) (400 mg, 0.93 mmol), tert-butyl (3-tri n-Butylstannylcyclopent-2-en-1-yl) carbamate (568 mg, 1.20 mmol) was dissolved in 1,4-dioxane (10 ml), and lithium chloride (118 mg, 2.78 mmol), 2 at room temperature. , 6-Ditert-butyl-p-cresol (4 mg, 0.02 mmol) and tetrakis (triphenylphosphine) palladium (0) (107 mg, 0.09 mmol) were added. The mixture was stirred at 100 ° C. for 24 hours under a nitrogen stream, and then cooled to room temperature. The insoluble material was filtered off while washing with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was fractionated with ethyl acetate and saturated brine. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (6.6 ml), water (0.3 ml) and potassium fluoride (976 mg) were added, and the mixture was vigorously stirred at room temperature for 4 hours. The insoluble material was filtered off while washing with dichloromethane, and the filtrate was concentrated under reduced pressure. Again, the resulting insoluble material was filtered off in the same manner, and the residue obtained by distilling off the solvent of the filtrate was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 2: 1, v / v), 155 mg (36%) of the title compound was obtained as a colorless gel.

MS (FAB) m / z: 466 (M + 1) ⁺ .
HRMS (FAB) m / z: 466.2127 (Calcd for C 29 H 28 N 3 O 3 466.2130).
¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.50-1.65 (2H, d, J = 6.6 Hz), 2.20-2.40 (3H, m) , 2.43 (3H, s), 4.74 (1H, br), 5.67 (1H, br s), 7.18 (2H, d, J = 6.6 Hz), 7.32 (1H, dd, J = 4.9, 7.6 Hz), 7.39-7.50 (3H, m), 8.03 (1H, br), 8.47 (1H, dd, J = 1.7, 4) .9 Hz).
IR (ATR): 3406, 2227, 1705, 1493, 1392, 1365, 1225, 1163, 768, 754, 710 cm ⁻¹ .

[Example 13]
5- [3- (Dimethylamino) cyclopent-1-en-1-yl] -7-methyl-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (# 13)

tert-Butyl [3- (8-cyano-7-methyl-6-phenyl [1] benzofuro [2,3-b] pyridin-5-yl) cyanopent-2-en-1-yl] carbamate (I-51 ) (495 mg, 1.06 mmol) was dissolved in 4N hydrochloric acid 1,4-dioxane solution (9 ml) and stirred at room temperature for 2 hours. Tetrahydrofuran was added to the residue obtained by distilling off the solvent under reduced pressure, followed by azeotropic distillation. This operation was repeated once more. The ocherous solid thus obtained was dried under reduced pressure, ethyl acetate and 1N aqueous sodium hydroxide solution were added to the solid, and the mixture was vigorously stirred for 10 minutes. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was dried under reduced pressure and used in the next reaction without purification.
Methanol (10 ml) was added to the ocherous solid obtained above, and a 37% formaldehyde solution (516 μl, 6.36 mmol), acetic acid (378 μl, 6.36 mmol) and cyanoborohydride were sequentially added to this suspension at 0 ° C. Sodium acid (240 mg, 3.82 mmol) was added. The temperature was gradually raised from 0 ° C. to room temperature, and the mixture was stirred at the same temperature for 17 hours. Chloroform and 1N aqueous sodium hydroxide solution were added to the reaction solution, and the mixture was vigorously stirred at room temperature for 30 minutes. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After separation by filtration, the residue obtained by distilling off the solvent was purified using medium pressure liquid chromatography (eluent; chloroform: methanol = 85: 15, v / v), and the resulting light brown solid was obtained. Was washed with diisopropyl ether to obtain 276 mg (66%) of the title compound as a white powder.

MS (ESI) m / z: 394 (M + 1) ^<+> .
HRMS (EI) m / z: 393.1837 (Calcd for C 26 H 23 N 3 O 393.1841).
¹ H-NMR (CDCl ₃ ) δ: 1.60-1.80 (2H, m), 1.90-2.50 (8H, m), 2.40 (3H, s), 3.50-4 .20 (1H, br), 5.75 (1H, q, J = 2.0 Hz), 7.14-7.20 (2H, m), 7.33 (1H, dd, J = 4.9, 7.6 Hz), 7.35-7.44 (3 H, m), 8.09 (1 H, br s), 8.48 (1 H, dd, J = 1.7, 4.9 Hz).
IR (ATR): 2769, 2226, 1392, 1338, 1209, 1039, 976, 910, 902, 768, 721 cm ⁻¹ .
Anal. _{Calcd for C 26 H 23 N 3} O · 0.25H 2 O: C, 78.47; H, 5.95; N, 10.56. Found: C, 78.52; H, 5.74; N, 10.40.

[Reference Example 52]
tert-Butyl 4- (8-cyano-7-methyl-6-phenyl [1] benzofuro [2,3-b] pyridin-5-yl) -3,6-dihydropyridine-1 (2H) -carboxylate (I -52)
Toluene of 8-cyano-7-methyl-6-phenyl [1] benzofuro [2,3-b] pyridin-5-yl trifluoromethanesulfonate (I-50) (1.0 g, 2.31 mmol) under nitrogen atmosphere To the solution (20 ml) was added lithium chloride (294 mg, 6.94 mmol), tert-butyl 4- (tri-n-butylstannyl) -3,6-dihydropyridine-1 (2H) -carboxylate (1.4 g, 3.01 mmol). And tetrakis (triphenylphosphine) palladium (0) (267 mg, 0.23 mmol) were added, and the mixture was heated to reflux for 20 hours. The reaction solution was returned to room temperature, and the insoluble material was removed by filtration through celite. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography, and eluted with a mixed solvent of n-hexane-ethyl acetate (100: 0 → 4: 1 → 3: 1, v / v). To give 150 mg (14%) of the title compound as a white solid.
MS (FAB) m / z: 466 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.77 (1H, br s), 2.27 (1H, br s), 2.44 (3H, s), 2. 73-2.85 (1H, m), 3.68 (1 H, td, J = 4.6, 13.2 Hz), 3.72-3.77 (1 H, m), 4.15-4.25 (1H, m), 5.68-5.77 (1H, m), 7.15 (2H, t, J = 7.3 Hz), 7.30-7.45 (4H, m), 8.12 (1H, d, J = 7.6 Hz), 8.49 (1H, dd, J = 1.7, 4.9 Hz).

[Example 14]
7-methyl-6-phenyl-5- (1,2,3,6-tetrahydropyridin-4-yl) [1] benzofuro [2,3-b] pyridine-8-carbonitrile (# 14)

  tert-Butyl 4- (8-cyano-7-methyl-6-phenyl [1] benzofuro [2,3-b] pyridin-5-yl) -3,6-dihydropyridine-1 (2H) -carboxylate (I -52) (149 mg, 0.32 mmol) was added 4N hydrochloric acid 1,4-dioxane solution (3.0 ml), and the mixture was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure and azeotroped with ethanol. The obtained residue was recrystallized from ethyl acetate-n-hexane-diisopropyl ether to obtain 103 mg (73%) of the title compound as a white solid.

MS (FAB) m / z: 366 (M + 1) ⁺ .
¹ H-NMR (DMSO-d ₆ ) δ: 1.84-1.90 (1H, m), 2.34 (1H, br s), 2.37 (3H, s), 2.57 (1H, br s), 3.30 (1H, br s), 3.44 (1H, br s), 3.77 (1H, br s), 5.82 (1H, br s), 7.26 (2H, d, J = 14.2 Hz), 7.42-7.51 (4H, m), 8.53 (1H, dd, J = 1.5, 4.9 Hz), 8.74 (1H, dd, J = 1.6, 7.7 Hz).
IR (ATR): 2721, 2225, 1587, 1390 cm ⁻¹ .
Anal. _{Calcd for C 24 H 19 N 3} O · 1.75H 2 O · HCl: C, 66.51; H, 5.47; N, 9.69; Cl, 8.18. Found: C, 66.78; H, 5.17; N, 9.64; Cl, 8.03.

[Reference Example 53]
5-Bromo-4-fluoro-2-hydroxybenzoic acid (I-53)
A solution prepared by dissolving 4-fluoro-2-hydroxybenzoic acid (29.01 g, 0.186 mol) in acetic acid (290 ml) and bromine (31.18 g, 0.195 mol) in acetic acid (15 ml) was obtained at room temperature. Drip slowly over time. The solution was stirred at 60 ° C. for 24 hours and then cooled to room temperature. The residue obtained by concentrating the reaction solution under reduced pressure was dissolved in methanol (100 ml) and poured into water (600 ml). After stirring for 15 minutes at room temperature, the precipitated crystals were collected after washing with water and dried to give 35.36 g (93%) of the title compound as a colorless solid.
¹ H-NMR (DMSO-d ₆ ) δ: 7.03 (1H, d, J = 10.3 Hz), 7.98 (1H, d, J = 8.1 Hz).

[Reference Example 54]
5-Bromo-4-fluoro-2-hydroxy-3-nitrobenzoic acid (I-54)
5-Bromo-4-fluoro-2-hydroxybenzoic acid (I-53) (34.39 g, 0.146 mol) was dissolved in concentrated sulfuric acid (260 ml) and cooled to 0 ° C. At the same temperature, fuming nitric acid (d = 1.52) (6.67 ml, 0.161 mol) was added dropwise over 20 minutes while maintaining the internal temperature at 10 ° C. or lower. After completion of the dropwise addition, after confirming disappearance of the raw material by TLC, the reaction solution was slowly poured onto ice. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. N-hexane was added to the residue obtained by distilling off the solvent under reduced pressure, and the crystals were pulverized and stirred as a suspension at room temperature for about 1 hour (sonication was also performed as needed). The crystals were washed after washing with n-hexane and dried to obtain 33.82 g (83%) of the title compound as an orange solid.
MS (ESI) m / z: 280, 282 (M + 1).
HRMS (EI) m / z: 278.9169 (Calcd for C 7 H 2 79 BrNO 5 278.9170).
¹ H-NMR (CDCl ₃ ) δ: 6.08 (1H, br), 8.29 (1H, d, J = 7.3 Hz), 11.31 (1H, br s).
IR (ATR): 3076, 2860, 1668, 1541, 1431, 1228, 1213, 1167, 1072, 685, 654 cm ⁻¹ .

[Reference Example 55]
Methyl 5-bromo-4-fluoro-2-methoxy-3-nitrobenzoate (I-55)
5-Bromo-4-fluoro-2-hydroxy-3-nitrobenzoic acid (I-54) (35.89 g, 0.128 mol) was dissolved in acetonitrile (600 ml), and potassium carbonate (53.1 g, 53.1 g, 0.385 mol) was added, and then dimethyl sulfate (30.3 ml, 0.32 mol) was added dropwise. After stirring at 60 ° C. for 2.5 hours, the mixture was cooled to room temperature and insoluble matters were filtered off (washed with acetonitrile). The filtrate was concentrated under reduced pressure, water was added to the residue, and the mixture was stirred at room temperature. The precipitated crystals were washed with water and dried to obtain 36.5 g (92%) of the title compound as a pale yellow solid.
MS (EI) m / z: 307, 309 (M ^<+> ).
^{_{HRMS (EI) m / z:}} 306.9494 (Calcd for C 9 H 7 79 BrFNO 5 306.9492), 308.9481 (Calcd for C 9 H 7 81 BrFNO 5 308.9472).
¹ H-NMR (CDCl ₃ ) δ: 3.97 (3H, s), 4.00 (3H, s), 8.26 (1H, d, J = 7.6 Hz).
IR (ATR): 1722, 1537, 1296, 1255, 1147, 1078, 991, 673, 636 cm ⁻¹ .

[Reference Example 56]
Methyl 3-amino-5-bromo-4-fluoro-2-methoxybenzoate (I-56)
Methyl 5-bromo-4-fluoro-2-methoxy-3-nitrobenzoate (I-55) (1.0 g, 3.25 mmol) was dissolved in acetic acid (10 ml), and iron powder (544 mg, 9.74 mmol) was obtained at room temperature. ) And heated at 130 ° C. for 4 hours. After cooling to room temperature, the insoluble material was filtered off while washing with ethyl acetate. The organic layer of the filtrate was distilled off under reduced pressure, and the resulting residue was fractionated with ethyl acetate and 1N sodium hydroxide solution. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 4: 1, v / v), and 798 mg (88%) of the title compound was obtained. Obtained as a colorless gel.
MS (EI) m / z: 277, 279 (M ^<+> ).
HRMS (EI) m / z: 276.9759 (Calcd for C ₉ H ₉ ⁷⁹ BrFNO ₃ 276.9750), 278.9748 (Calcd for C ₉ H ₉ ⁸¹ BrFNO ₃ 278.9729).
¹ H-NMR (CDCl ₃ ) δ: 3.87 (3H, s), 3.90 (3H, s), 4.80 (2H, br s), 7.43 (1H, d, J = 7. 8 Hz).
IR (ATR): 3475, 1724, 1614, 1466, 1435, 1319, 1294, 1205, 1009, 924, 787 cm ⁻¹ .

[Reference Example 57]
Methyl 5-amino-6-fluoro-4-methoxybiphenyl-3-carboxylate (I-57)
Methyl 3-amino-5-bromo-4-fluoro-2-methoxybenzoate (I-56) (504 mg, 1.81 mmol) was dissolved in 1,4-dioxane (10 ml) and phenyl boron was dissolved at room temperature under a nitrogen stream. Acid (456 mg, 3.62 mmol), tripotassium phosphate (770 mg, 3.62 mmol), tetrakis (triphenylphosphine) palladium (0) (210 mg, 0.18 mmol) were added. The mixture was stirred at 90 ° C. for 36 hours and then cooled to room temperature. The insoluble material was filtered off while washing with ethyl acetate, and the filtrate was fractionated with ethyl acetate and saturated brine. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 3: 1, v / v), and 459 mg (92%) of the title compound was obtained. Obtained as a colorless gel.
MS (EI) m / z: 275 (M ^<+> ).
HRMS (EI) m / z: 275.0967 (Calcd for C 15 H 14 FNO 3 275.0958).
¹ H-NMR (CDCl ₃ ) δ: 3.90 (3H, s), 3.91 (3H, s), 4.02 (2H, br), 7.32-7.38 (2H, m), 7.39-7.45 (2H, m), 7.49-7.52 (2H, m).
IR (ATR): 3371, 1724, 1468, 1425, 1238, 1203, 1009, 700 cm ⁻¹ .

[Reference Example 58]
5-Amino-6-fluoro-4-methoxybiphenyl-3-carboxamide (I-58)
Methyl 5-amino-6-fluoro-4-methoxybiphenyl-3-carboxylate (I-57) (3.0 g, 10.90 mmol) was dissolved in tetrahydrofuran (90 ml) and water (45 ml) at 0 ° C. Lithium hydroxide monohydrate (4.57 g, 108.98 mmol) was added slowly. The mixture was heated to reflux for 5 hours and then cooled to room temperature. The residue obtained by distilling off the organic layer under reduced pressure was cooled to 0 ° C., and 2N hydrochloric acid (55 ml) was slowly added. After the addition, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure to give 5-amino-6-fluoro-4-methoxybiphenyl-3-carboxylic acid as a white solid. This product was dissolved in N, N-dimethylformamide (60 ml) without purification, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3.14 g, 16.35 mmol), 1 at room temperature. -Hydroxybenzotriazole (2.21 g, 16.35 mmol) and 28% aqueous ammonia (2.0 ml, 32.70 mmol) were slowly added. The solution was stirred at room temperature for 11 hours and then fractionated with ethyl acetate and saturated brine. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified using medium pressure liquid chromatography (eluent; chloroform: methanol = 98: 2, v / v) and 2.83 g (99.8%) of the title compound. Was obtained as a white solid.
MS (EI) m / z: 260 (M ^<+> ).
HRMS (EI) m / z: 260.0959 (Calcd for C 14 H 13 FN 2 O 2 260.0961).
¹ H-NMR (CDCl ₃ ) δ: 3.87 (3H, s), 4.02 (2H, br s), 6.67 (1H, br s), 7.32-7.44 (3H, m ), 7.51-7.65 (4H, m).
IR (ATR): 3452, 3336, 3190, 1662, 1618, 1579, 1464, 1396, 1240, 1020, 752, 698 cm ⁻¹ .

[Reference Example 59]
N- (5-cyano-2-fluoro-4-methoxybiphenyl-3-yl) -2,2,2-trifluoroacetamide (I-59)
5-Amino-6-fluoro-4-methoxybiphenyl-3-carboxamide (I-58) (2.28 g, 8.76 mmol) was dissolved in tetrahydrofuran (36 ml), and triethylamine (4.88 ml, 35) was dissolved at 0 ° C. 0.04 mmol) and trifluoroacetic anhydride (3.71 ml, 26.28 mmol) in tetrahydrofuran (10 ml) were slowly added. After stirring at 0 ° C. for 2 hours, water (46 ml) was added and stirred vigorously for 5 minutes. Tetrahydrofuran was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 4: 1, v / v) to give 2.782 g (94% of the title compound). ) Was obtained as a white solid.
MS (FAB) m / z: 339 (M + 1) ^<+> .
HRMS (FAB) m / z: 339.0760 (Calcd for C 16 H 11 F 4 N 2 O 2 339.0757).
¹ H-NMR (CDCl ₃ ) δ: 4.16 (3H, s), 7.39-7.50 (5H, m), 7.63 (1H, d, J = 7.8 Hz), 8.03 (1H, br s).
IR (ATR): 3232, 2231, 1726, 1479, 1433, 1417, 1207, 1153, 1059, 958, 908, 766, 692 cm ⁻¹ .

[Reference Example 60]
5-Amino-6-fluoro-4-methoxybiphenyl-3-carbonitrile (I-60)
N- (5-cyano-2-fluoro-4-methoxybiphenyl-3-yl) -2,2,2-trifluoroacetamide (I-59) (2.78 g, 8.22 mmol) was added to methanol (31. 8 ml) and a 15 wt% aqueous potassium carbonate solution (31.8 ml, 34.5 mmol) was added at room temperature. The mixture was stirred at 70 ° C. for 38 hours. After cooling to room temperature, methanol was distilled off under reduced pressure, and the resulting residue was extracted with ethyl acetate. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 4: 1, v / v), and 1.833 g (92%) of the title compound was obtained. ) Was obtained as a colorless gel.
MS (EI) m / z: 242 (M ^<+> ).
HRMS (EI) m / z: 242.0854 (Calcd for C 14 H 11 FN 2 O 242.0855).
¹ H-NMR (CDCl ₃ ) δ: 4.09 (3H, s), 4.05-4.20 (2H, br), 7.00 (1H, d, J = 8.1 Hz), 7.38 -7.49 (5H, m).
IR (ATR): 3477, 3367, 2229, 1618, 1481, 1470, 1427, 1254, 1188, 1170, 1153, 1049, 1001, 770, 698 cm ⁻¹ .

[Reference Example 61]
5-Amino-2-bromo-6-fluoro-4-methoxybiphenyl-3-carbonitrile (I-61)
5-Amino-6-fluoro-4-methoxybiphenyl-3-carbonitrile (I-60) (500 mg, 2.06 mmol) was dissolved in acetic acid (9.5 ml), and N-bromosuccinimide (441 mg) was slowly added at room temperature. , 2.48 mmol). After stirring for 1 hour at room temperature under a nitrogen stream, the solvent was distilled off under reduced pressure. The residue was fractionated with ethyl acetate and 1N aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After separation by filtration, the residue obtained by distilling off the solvent was purified using medium-pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 3: 1, v / v), and 592 mg of the title compound ( 89%) was obtained as a light brown solid.
MS (EI) m / z: 320, 322 (M ^<+> ).
HRMS (EI) m / z: 319.9984 (Calcd for C 14 H 10 Br 79 FN 2 O 319.9960), 321.9958 (Calcd for C 14 H 10 Br 81 FN 2 O 321.9940).
¹ H-NMR (CDCl ₃ ) δ: 4.05-4.10 (2H, br), 4.08 (3H, s), 7.24-7.29 (2H, m), 7.42-7 .50 (3H, m).
IR (ATR): 3369, 2231, 1616, 1465, 1452, 1434, 1417, 1190, 1155, 1061, 1011, 937, 775, 716, 698 cm ⁻¹ .

[Reference Example 62]
N- (6-Bromo-5-cyano-6-fluoro-4-methoxybiphenyl-3-yl) -2,2,2, -trifluoroacetamide (I-62)
5-Amino-2-bromo-6-fluoro-4-methoxybiphenyl-3-carbonitrile (I-61) (500 mg, 1.56 mmol) was dissolved in tetrahydrofuran (5 ml). To this solution, a solution of triethylamine (651 μl, 4.67 mmol) and trifluoroacetic anhydride (330 μl, 2.34 mmol) in tetrahydrofuran (5 ml) was slowly added dropwise at 0 ° C. under a nitrogen stream. After stirring at 0 ° C. for 3 hours, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution at the same temperature, and the mixture was further stirred for 10 minutes. The organic solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography using silica gel (eluent; n-hexane: ethyl acetate = 4: 1, v / v), and 605 mg (93%) of the title compound was palely added. Obtained as a brown solid.
MS (ESI) m / z: 417, 419 (M + 1) ⁺ .
HRMS (EI) m / z: 415.9772 (Calcd for C ₁₆ H ₉ ⁷⁹ BrF ₄ N ₂ O ₂ 415.9783), 417.9763 (Calcd for C ₁₆ H ₉ ⁸¹ BrF ₄ N ₂ O ₂ 417.9763 ).
¹ H-NMR (CDCl ₃ ) δ: 4.19 (3H, s), 7.26-7.29 (2H, m), 7.47-7.51 (3H, m), 7.67 (1H , Br s).
IR (ATR): 3250, 2237, 1732, 1408, 1213, 1155 cm ⁻¹ .

[Reference Example 63]
N- (5-cyano-2-fluoro-4-methoxy-6-vinylbiphenyl-3-yl) -2,2,2, -trifluoroacetamide (I-63)
N- (6-Bromo-5-cyano-6-fluoro-4-methoxybiphenyl-3-yl) -2,2,2, -trifluoroacetamide (I-62) (100 mg, 0.24 mmol), tri n-Butyl (vinyl) tin (91 μl, 0.31 mmol), lithium chloride (31 mg, 0.72 mmol) and 2,6-ditert-butyl-p-cresol (2 grains) in 1,4-dioxane (3 ml) In a nitrogen stream, room temperature tetrakis (triphenylphosphine) palladium (0) (28 mg, 0.024 mmol) was added. The reaction was stirred at 100 ° C. for 8 hours and then cooled to room temperature. The insoluble material was filtered off while washing with ethyl acetate, and the filtrate was washed with saturated brine and dried over anhydrous sodium sulfate. After separation by filtration, the residue obtained by evaporating the solvent was dissolved in dichloromethane (3 ml), and water (0.15 ml) and potassium fluoride (90 mg, 1.55 mmol) were successively added to this solution. After vigorous stirring at room temperature for 4 hours, the insoluble material was filtered off while washing with dichloromethane. The filtrate was concentrated under reduced pressure, and the residue was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 4: 1, v / v), and 67 mg (77%) of the title compound was obtained as a colorless gel. Got as.
MS (ESI) m / z: 365 (M + 1) ⁺ .
HRMS (EI) m / z: 364.0860 (Calcd for C 18 H 12 F 4 N 2 O 2 364.0835).
¹ H-NMR (CDCl ₃ ) δ: 4.10 (3H, s), 5.59 (1H, d, J = 11.7 Hz), 5.77 (1H, d, J = 17.8 Hz), 6 .43 (1H, dd, J = 11.7, 17.8 Hz), 7.20-7.25 (2H, m), 7.40-7.48 (3H, m), 7.97 (1H, br s).
IR (ATR): 3234, 3035, 2231, 1732, 1527, 1470, 1402, 1215, 1153, 1088, 698 cm ⁻¹ .

[Reference Example 64]
N- (5-cyano-6-ethyl-2-fluoro-4-methoxybiphenyl-3-yl) -2,2,2-trifluoroacetamide (I-64)
N- (5-cyano-2-fluoro-4-methoxy-6-vinylbiphenyl-3-yl) -2,2,2, -trifluoroacetamide (I-63) (100 mg, 0.28 mmol) was acetic acid Dissolved in ethyl (2 ml), 10% palladium on carbon (20 mg) was added to the solution. The suspension was stirred at room temperature under a normal pressure hydrogen stream for 5 hours. The catalyst was filtered off with washing with ethyl acetate. The residue obtained by concentrating the filtrate under reduced pressure was then purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 4: 1, v / v) to give 98 mg (97% of the title compound). ) Was obtained as a colorless gel.
MS (ESI) m / z: 367 (M + 1) ^<+> .
HRMS (EI) m / z: 366.0987 (Calcd for C 18 H 14 F 4 N 2 O 2 366.0992).
¹ H-NMR (CDCl ₃ ) δ: 1.09 (3H, t, J = 7.6 Hz), 2.69 (2H, q, J = 7.6 Hz), 7.20-7.23 (2H, m), 7.41-7.50 (3H, m), 7.96 (1H, brs).
IR (ATR): 2229, 1728, 1529, 1471, 1421, 1213, 1153, 1101, 708 cm ⁻¹ .

[Reference Example 65]
5-Amino-2-ethyl-6-fluoro-4-methoxybiphenyl-3-carbonitrile (I-65)
N- (5-cyano-6-ethyl-2-fluoro-4-methoxybiphenyl-3-yl) -2,2,2-trifluoroacetamide (I-64) (842 mg, 2.30 mmol) was added to methanol ( 8.5 ml), and an aqueous potassium carbonate solution (a solution in which 15 g of potassium carbonate was dissolved in water to make 100 ml) (8.5 ml, 9.19 mmol) was added at room temperature. The solution was stirred at 70 ° C. for 18 hours and then cooled to room temperature. The organic solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 4: 1, v / v), and 541 mg (87%) of the title compound was white. Obtained as a solid.
MS (ESI) m / z: 271 (M + 1) ⁺ .
HRMS (EI) m / z: 270.1167 (Calcd for C 16 H 15 FN 2 O 270.1168).
¹ H-NMR (CDCl ₃ ) δ: 1.03 (3H, t, J = 7.6 Hz), 2.57 (2H, q, J = 7.6 Hz), 3.90 (2H, br s), 4.05 (3H, s), 7.20-7.26 (2H, m), 7.39-7.49 (3H, m).
IR (ATR): 3452, 3363, 2225, 1626, 1572, 1475, 1452, 1433, 1358, 1286, 1198, 1159, 1036, 935, 879, 754, 704 cm ⁻¹ .

[Reference Example 66]
5-Bromo-2-ethyl-6-fluoro-4-methoxybiphenyl-3-carbonitrile (I-66)
Copper (II) bromide (982 mg, 4.4 mmol) was dissolved in acetonitrile (4 ml), and tert-butyl nitrite (purity 90%, 528 μl, 4.0 mmol) was added at room temperature under a nitrogen stream. After the solution was stirred at 60 ° C. for 10 minutes, 5-amino-2-ethyl-6-fluoro-4-methoxybiphenyl-3-carbonitrile (I-65) (540 mg, 2.0 mmol) was added to acetonitrile (6 ml). ) Was slowly added to the solution. After stirring at the same temperature for 2 hours, the mixture was cooled to room temperature. The reaction mixture was fractionated with ethyl acetate and 1N aqueous hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 9: 1, v / v), and 596 mg (89%) of the title compound was white. Obtained as a solid.
HRMS (EI) m / z: 333.0163 (Calcd for C ₁₆ H ₁₃ ⁷⁹ BrFNO 333.0165), 335.0147 (Calcd for C ₁₆ H ₁₃ ⁸¹ BrFNO 335.0144).
¹ H-NMR (CDCl ₃ ) δ: 1.08 (3H, t, J = 7.6 Hz), 2.67 (2H, q, J = 7.6 Hz), 4.11 (3H, s), 7 20-7.25 (2H, m), 7.43-7.51 (3H, m).
IR (ATR): 2225, 1412, 1095, 1049, 957, 744, 700 cm ⁻¹ .

[Reference Example 67]
2-Ethyl-6-fluoro-5- (2-fluoropyridin-3-yl) -4-methoxybiphenyl-3-carbonitrile (I-67)
5-Bromo-2-ethyl-6-fluoro-4-methoxybiphenyl-3-carbonitrile (I-66) (596 mg, 1.78 mmol), 2-fluoro-3- (4,4,5,5-tetra Methyl [1,3,2] dioxaboran-2-yl) pyridine (796 mg, 3.57 mmol) and cesium carbonate (1.162 g, 3.57 mmol) were suspended in toluene (12 ml), and tetrakis at room temperature under a nitrogen stream. (Triphenylphosphine) palladium (0) (206 mg, 0.18 mmol) was added. The suspension was heated to reflux for 16 hours and then cooled to room temperature. The insoluble material was filtered off while washing with ethyl acetate. The filtrate was washed with saturated brine and dried over anhydrous sodium sulfate. After separation by filtration, the residue obtained by distilling off the solvent was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 4: 1, v / v), and 546 mg (87 of the title compound) %) As a colorless gel.
MS (ESI) m / z: 351 (M + 1) ⁺ .
HRMS (EI) m / z: 350.1223 (Calcd for C 21 H 16 F 2 N 2 O 350.1231).
¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.6 Hz), 2.75 (2H, q, J = 7.6 Hz), 3.84 (3H, s), 7 .25-7.33 (3H, m), 7.40-7.50 (3H, m), 7.83 (1H, ddd, J = 2.0, 7.6, 9.0 Hz), 8. 29-8.31 (1H, m).
IR (ATR): 2225, 1564, 1406, 1097, 1049, 795, 756, 708 cm ⁻¹ .

[Reference Example 68]
7-Ethyl-5-fluoro-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-68)
2-ethyl-6-fluoro-5- (2-fluoropyridin-3-yl) -4-methoxybiphenyl-3-carbonitrile (I-67) (545 mg, 1.56 mmol) dissolved in dimethyl sulfoxide (11 ml) Then, triethylamine (650 μl, 4.67 mmol) was added at room temperature under a nitrogen stream. The temperature was gradually raised from room temperature to 120 ° C., and the mixture was stirred at the same temperature for 12 hours. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure. The residue was fractionated with ethyl acetate and saturated brine. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After separation by filtration, the residue obtained by evaporating the solvent was purified by column chromatography using silica gel (eluent; n-hexane: ethyl acetate = 4: 1, v / v), and 432 mg of the title compound ( 88%) was obtained as a white solid.
MS (ESI) m / z: 317 (M + 1) ^<+> .
HRMS (EI) m / z: 316.1011 (Calcd for C 20 H 13 FN 2 O 316.1012).
¹ H-NMR (CDCl ₃ ) δ: 1.16 (3H, t, J = 7.6 Hz), 2.87 (2H, q, J = 7.6 Hz), 7.30-7.33 (2H, m), 7.44 (1H, dd, J = 4.9, 7.6 Hz), 7.47-7.56 (3H, m), 8.33 (1H, dd, J = 1.7, 7) .6 Hz), 8.55 (1H, dd, J = 1.7, 4.9 Hz).
IR (ATR): 2224, 1597, 1400, 1306, 1227, 1043, 810, 698 cm ⁻¹ .

[Example 15]
5-[(3S) -3- (Dimethylamino) pyrrolidin-1-yl] -7-ethyl-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (# 15)

  7-ethyl-5-fluoro-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-68) (200 mg, 0.63 mmol) was dissolved in dimethyl sulfoxide (4 ml), Triethylamine (176 μl, 1.26 mmol) and (3S) -3- (dimethylamino) pyrrolidine (120 μl, 0.95 mmol) were added at room temperature. The suspension was stirred at 90 ° C. for 23 hours and then cooled to room temperature. Chloroform was added to this solution, and the solvent was distilled off under reduced pressure. The residue was fractionated with chloroform and saturated brine. The organic layer was separated and the aqueous layer was extracted twice with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After separation by filtration, the residue obtained by distilling off the solvent was purified using preparative TLC (developing solution; chloroform: methanol = 9: 1, v / v), and 149 mg (57%) of the title compound was pale brown. Obtained as a solid.

MS (ESI) m / z: 411 (M + 1) ⁺ .
HRMS (EI) m / z: 410.2109 (Calcd for C 26 H 26 N 4 O 410.2106).
¹ H-NMR (CDCl ₃ ) δ: 1.11 (3H, t, J = 7.6 Hz), 1.66-1.76 (1H, m), 2.01-2.10 (1H, m) 2.14 (6H, s), 2.59 (1H, quint, J = 7.6 Hz), 2.67-2.73 (1H, m), 2.70 (2H, q, J = 7. 6 Hz), 2.97-3.10 (3 H, m), 7.20-7.29 (2 H, m), 7.40 (1 H, dd, J = 4.9, 7.8 Hz), 7. 43-7.50 (3H, m), 8.10 (1H, dd, J = 1.7, 7.8 Hz), 8.45 (1H, dd, J = 1.7, 4.9 Hz).
IR (ATR): 2218, 1589, 152, 1456, 1394, 1367, 1207, 151, 761, 710 cm ⁻¹ .
Anal. _{Calcd for C 26 H 26 N 4} O · 0.5H 2 O: C, 74.44; H, 6.49; N, 13.35. Found: C, 74.54; H, 6.25; N, 13.29.

[Reference Example 69]
3-Amino-5-bromo-4-fluoro-2-methoxybenzoic acid (I-69)
To a solution of methyl 3-amino-5-bromo-4-fluoro-2-methoxybenzoate (I-56) (4.50 g, 16.2 mmol) in tetrahydrofuran (160 ml) under ice-cooling, lithium hydroxide monohydrate 6. A solution of 80 g (162 mmol) in water (70 ml) was added and stirred at 70 ° C. for 3.5 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and 2N aqueous hydrochloric acid (81 ml) was added to the resulting residue under ice cooling. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 4.01 g (94%) of the title compound as a light brown solid. Obtained.
MS (ESI) m / z: 264, 266 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 3.95 (3H, s), 3.99-4.10 (2H, m), 7.68 (1H, d, J = 7.8 Hz).
IR (ATR): 3471, 3369, 1672, 1608, 1585, 1469, 1423, 1309, 1261, 1230, 1211, 1155 cm ⁻¹ .

[Reference Example 70]
3-Amino-5-bromo-4-fluoro-2-methoxybenzoic acid amide (I-70)
3-Amino-5-bromo-4-fluoro-2-methoxybenzoic acid (I-69) (500 mg, 1.89 mmol) was suspended in thionyl chloride (1 ml), heated gradually and stirred at 95 ° C. for 2 hours. (It gradually dissolved when heated). After cooling to room temperature, the solvent was distilled off under reduced pressure. Toluene was added to the residue and azeotropic distillation was performed (performed twice). The residue was thoroughly dried under reduced pressure, dissolved by adding ethyl acetate (5 ml), and cooled to 0 ° C. 28% aqueous ammonia (2.5 ml) was slowly added at the same temperature. After stirring at the same temperature for 2 hours, the mixture was fractionated with ethyl acetate and saturated brine. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After separation by filtration, the residue obtained by evaporating the solvent was purified using medium pressure liquid chromatography (eluent; chloroform: methanol = 98: 2, v / v), and 464 mg (93%) of the title compound was obtained. Obtained as a white solid.
MS (EI) m / z: 262, 264 (M ^<+> ).
HRMS (EI) m / z: 261.9976 (Calcd for C ₈ H ₈ Br ⁷⁹ FN ₂ O ₂ 261.9753), 2633.9748 (Calcd for C ₈ H ₈ ⁸¹ BrFN ₂ O ₂ 263.732).
¹ H-NMR (CDCl ₃ ) δ: 3.70 (3H, s), 5.43 (2H, br s), 6.97 (1H, d, J = 7.6 Hz), 7.51 (1H, br s), 7.63 (1H, br s).
IR (ATR): 3458, 3336, 3149, 1685, 1577, 1456, 1392, 1146, 1016, 924 cm ⁻¹ .

[Reference Example 71]
3-Amino-5-bromo-4-fluoro-2-methoxybenzonitrile (I-71)
3-Amino-5-bromo-4-fluoro-2-methoxybenzoic acid amide (I-70) (1.346 g, 5.12 ml) was dissolved in tetrahydrofuran (26 ml), and triethylamine ( 2.14 ml, 15.35 mmol) A solution of trifluoroacetic anhydride (1.59 ml, 11.26 mmol) in tetrahydrofuran (14 ml) was then added dropwise. After stirring at the same temperature for 1.5 hours, water was added at 0 ° C. and stirred vigorously for 5 minutes. The residue obtained by evaporating the solvent under reduced pressure was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was distilled off under reduced pressure to obtain a light brown solid. This was dissolved in methanol (19 ml), aqueous potassium carbonate solution (15 g of potassium carbonate was added to make 100 ml) at room temperature, and stirred at 70 ° C. for 11 hours. The reaction was left at room temperature for 12 hours. After adding water, it was stirred vigorously for 5 minutes. While washing with water, 743 mg (59%) of light brown plate crystals were collected by filtration. The filtrate was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After separation by filtration, the residue obtained by distilling off the solvent under reduced pressure was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 4: 1, v / v) to give 101 mg of the title compound. (8%) was obtained as a white solid (total 844 mg, 67%).

MS (EI) m / z: 244,246 (M ^<+> ).
HRMS (EI) m / z: 243.9663 (Calcd for C 8 H 6 Br 79 FN 2 O 243.9648), 245.9642 (Calcd for C 8 H 6 81 BrFN 2 O 245.9627).
¹ H-NMR (CDCl ₃ ) δ: 4.06 (3H, s), 4.11 (2H, br s), 7.11 (1H, d, J = 7.1 Hz).
IR (ATR): 3464, 3354, 2233, 1612, 1462, 1427, 1263, 1207, 1153, 1047, 999, 924, 825, 775 cm ⁻¹ .

[Reference Example 72]
3-Amino-5-bromo-4-fluoro-6-iodo-2-methoxybenzonitrile (I-72)
To a solution of 3-amino-5-bromo-4-fluoro-2-methoxybenzonitrile (I-71) (6.43 g, 26.2 mmol) in acetic acid (260 ml) was added N-iodosuccinimide (7.08 g) under water cooling. 31.5 mmol) and stirred at room temperature for 22.5 hours. After the reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in chloroform, the organic layer was washed with 1N aqueous sodium hydroxide solution, and the aqueous layer was extracted with chloroform. The combined organic layers were then dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was suspended and washed with diisopropyl ether to give 5.96 g (61%) of the title compound as a light brown solid. The filtrate was concentrated under reduced pressure, and the obtained residue was suspended and washed again with diisopropyl ether to obtain 1.51 g of the title compound, giving a total of 7.47 g (77%) of the title compound. It was.
MS (ESI) m / z: 371, 373 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 4.02 (3H, s), 4.15 (2H, brs).
IR (ATR): 3473, 3361, 2233, 1614, 1468, 1437, 1410, 1290, 1151 cm ⁻¹ .

[Reference Example 73]
3-Amino-5-bromo-4-fluoro-2-methoxy-6-methylbenzonitrile (I-73)
Under a nitrogen atmosphere, 3-amino-5-bromo-4-fluoro-6-iodo-2-methoxybenzonitrile (I-72) (4.88 g, 13.2 mmol), trimethylboroxine (50% tetrahydrofuran solution) ( 3.30 ml, 13.2 mmol), potassium carbonate (3.65 g, 26.4 mmol) and tetrakis (triphenylphosphine) palladium (0) (1.53 g, 1.32 mmol) in 1,4-dioxane-water (66 ml) -6.6 ml) The mixed solution was stirred at 110 ° C for 135 hours. After cooling, the reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 1.02 g (30%) of the title compound was obtained as a yellow solid from a fraction eluted with n-hexane-ethyl acetate (5: 1, v / v). The ethyl acetate eluate and the solid residue remaining on the silica gel were combined and the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and n-hexane-ethyl acetate (5: 1). , V / v) 1.00 g of the title compound was obtained from the elution portion, and 2.02 g (59%) of the title compound was obtained in total.
MS (ESI) m / z: 259, 261 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H, s), 3.95 (2H, brs), 4.00 (3H, s).
IR (ATR): 3477, 3365, 2227, 1614, 1477, 1450, 1346, 1261, 1153, 1057 cm ⁻¹ .

[Reference Example 74]
5-Amino-6-fluoro-4-methoxy-2-methyl-3'-nitrobiphenyl-3-carbonitrile (I-74)
Under a nitrogen atmosphere, 3-amino-5-bromo-4-fluoro-2-methoxy-6-methylbenzonitrile (I-73) (1.02 g, 3.94 mmol), 3-nitrophenylboronic acid (986 mg, 5 .91 mmol), tripotassium phosphate (1.67 g, 7.88 mmol) and tetrakis (triphenylphosphine) palladium (0) (455 mg, 394 μmol) in 1,4-dioxane (20 ml) were heated for 62 hours. Refluxed. After cooling, the reaction solution was diluted with ethyl acetate, filtered, and the filtrate was washed with water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 831 mg of the title compound containing impurities was obtained as a yellow solid from the eluate of n-hexane-ethyl acetate (4: 1, v / v).
MS (ESI) m / z: 302 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.23 (3H, s), 3.95 (2H, brs), 4.08 (3H, s), 7.55-7.59 (1H, m), 7.62-7.68 (1H, m), 8.12-8.14 (1H, m), 8.25-8.31 (1H, m).

[Reference Example 75]
5-Bromo-6-fluoro-4-methoxy-2-methyl-3'-nitrobiphenyl-3-carbonitrile (I-75)
Under a nitrogen atmosphere, tert-butyl nitrite (655 μl, 5.50 mmol) was added to a suspension of copper bromide (1.35 g, 6.05 mmol) in acetonitrile (18 ml), and then at 60 ° C., Reference Example 74 A suspension of 5-amino-6-fluoro-4-methoxy-2-methyl-3′-nitrobiphenyl-3-carbonitrile (I-74) (829 mg) obtained in 1 above in acetonitrile (10 ml) was added dropwise. Stir at temperature for 5 hours. After cooling, the reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was suspended and washed with diethyl ether to give 768 mg of the crude title compound as an orange solid.
¹ H-NMR (CDCl ₃ ) δ: 2.33 (3H, s), 4.14 (3H, s), 7.55-7.60 (1H, m), 7.66-7.73 (1H M), 8.12-8.16 (1H, m), 8.29-8.38 (1H, m).

[Reference Example 76]
N- (3′-bromo-5′-cyano-2′-fluoro-4′-methoxy-6′-methylbiphenyl-3-yl) acetamide (I-76)
5-Bromo-6-fluoro-4-methoxy-2-methyl-3′-nitrobiphenyl-3-carbonitrile (I-75) (764 mg) and iron powder (351 mg, 6.28 mmol) obtained in Reference Example 75 Of acetic acid (21 ml) was heated to reflux for 17 hours. After cooling, the reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. Next, a saturated aqueous sodium hydrogen carbonate solution was added to the obtained residue, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 731 mg of the title compound containing impurities was obtained as an amorphous form from a fraction eluted with n-hexane-ethyl acetate (1: 1, v / v).
MS (ESI) m / z: 377, 379 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 2.19 (3H, s), 2.31 (3H, s), 4.11 (3H, s), 6.92-6.96 (1H, m), 7.39-7.74 (3H, m).

[Reference Example 77]
3′-Amino-5-bromo-6-fluoro-4-methoxy-2-methylbiphenyl-3-carbonitrile (I-77)
N- (3′-bromo-5′-cyano-2′-fluoro-4′-methoxy-6′-methylbiphenyl-3-yl) acetamide (I-76) (729 mg) ethanol obtained in Reference Example 76 Concentrated hydrochloric acid (6 ml) was added to the (10 ml) solution and stirred at 70 ° C. for 4 hours. After cooling, 1N aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with a chloroform-methanol (10: 1, v / v) mixture. Next, the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 444 mg of the title compound containing impurities was obtained as a milky white solid from a fraction eluted with n-hexane-ethyl acetate (2: 1, v / v).
MS (ESI) m / z: 335, 337 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 2.32 (3H, s), 3.77 (2H, brs), 4.10 (3H, s), 6.48-6.50 (1H, m), 6.54-6.57 (1H, m), 6.72-6.77 (1H, m), 7.23 (1H, d, J = 8.1 Hz).

[Reference Example 78]
3′-Amino-6-fluoro-5- (2-fluoropyridin-3-yl) -4-methoxy-2-methylbiphenyl-3-carbonitrile (I-78)
Under a nitrogen atmosphere, 3′-amino-5-bromo-6-fluoro-4-methoxy-2-methylbiphenyl-3-carbonitrile (I-77) (439 mg) obtained in Reference Example 77, 2-fluoro-3 -(4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) pyridine (438 mg, 1.96 mmol), cesium carbonate (854 mg, 2.62 μmol) and tetrakis (triphenylphosphine) A suspension of palladium (0) (76 mg, 66 μmol) in toluene (7 ml) was heated to reflux for 17 hours. After cooling, the reaction solution was diluted with ethyl acetate, filtered, and the filtrate was washed with water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 352 mg of the title compound containing impurities was obtained as an amorphous form from a fraction eluted with n-hexane-ethyl acetate (1: 2, v / v).
MS (ESI) m / z: 352 (M + 1) ^<+> .

[Example 16]
6- (3-Aminophenyl) -5-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -7-methyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile ( # 16)

  3'-amino-6-fluoro-5- (2-fluoropyridin-3-yl) -4-methoxy-2-methylbiphenyl-3-carbonitrile (I-78) (352 mg) containing impurities under nitrogen atmosphere And triethylamine (338 μl, 3.00 mmol) in dimethyl sulfoxide (10 ml) were stirred at 130 ° C. for 18 hours, and (3S) -3- (dimethylamino) pyrrolidine (254 μl, 2.00 mmol) was stirred at the same temperature. After the addition, the mixture was further stirred for 6.5 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform. Next, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, and then the aqueous layer was extracted with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give the crude title compound from the eluate of dichloromethane-methanol (10: 1, v / v), and recrystallized from ethanol to give 44 mg of the title compound as a pale yellow solid. Obtained.

mp: 255-257 ° C.
MS (ESI) m / z: 412 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.68-1.80 (1H, m), 2.03-2.11 (1H, m), 2.17 (6H, s), 2.37 (3H , D, J = 1.7 Hz), 2.60-2.70 (1H, m), 2.80-2.91 (1H, m), 3.04-3.20 (3H, m), 6 .46-6.60 (2H, m), 6.71-6.76 (1H, m), 7.23 (1H, d, J = 7.8 Hz), 7.40 (1H, dd, J = 7.8, 4.9 Hz), 8.07-8.12 (1 H, m), 8.46 (1 H, dd, J = 4.9, 1.5 Hz).
IR (ATR): 3450, 3313, 3192, 2220, 1585, 1464, 1389, 1363, 1211, 1157 cm ⁻¹ .
Anal. _{Calcd for C 25 H 25 N 5} O: C, 72.97; H, 6.12; N, 17.02. Found: C, 72.61; H, 6.09; N, 16.88.

[Reference Example 79]
N- (3-Bromo-5-cyano-2-fluoro-6-methoxy-4-methylphenyl) -2,2,2-trifluoroacetamide (I-79)
Under a nitrogen atmosphere, 3-amino-5-bromo-4-fluoro-2-methoxy-6-methylbenzonitrile (I-73) (2.05 g, 7.91 mmol) and triethylamine (2.20 ml, 15.8 mmol) To a tetrahydrofuran (30 ml) solution of trifluoroacetic anhydride (1.68 ml, 11.9 mmol) in tetrahydrofuran (10 ml) was added dropwise at 0 ° C. and stirred at room temperature for 17 hours. Saturated brine was added under ice cooling, and the mixture was stirred at room temperature, and then the mixture was extracted with ethyl acetate. Next, the combined organic layers were dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 2.53 g (90%) of the title compound was obtained as a white solid from a fraction eluted with n-hexane-ethyl acetate (4: 1, v / v).
¹ H-NMR (CDCl ₃ ) δ: 2.68 (3H, s), 4.10 (3H, s), 7.61 (1H, brs).
IR (ATR): 3215, 2231, 1730, 1531, 1471, 1410, 1338, 1180, 1149 cm ⁻¹ .

[Reference Example 80]
3-Amino-4-fluoro-2-methoxy-6-methyl-5- (pyridin-2-yl) benzonitrile (I-80)
Under a nitrogen atmosphere, N- (3-bromo-5-cyano-2-fluoro-6-methoxy-4-methylphenyl) -2,2,2-trifluoroacetamide (I-79) (200 mg, 563 μmol)) , Tri-n-butyl (2-pyridyl) tin (311 mg, 845 μmol) and 2,6 di-tert-butyl-p-cresol (5 tablets) in toluene (6 ml) were dissolved in dichlorobis (triphenylphosphine) palladium (II). ) (40 mg, 56 μmol) was added and the mixture was heated to reflux for 19.5 hours. After cooling, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and a white solid was obtained from the eluate of n-hexane-ethyl acetate (1: 1, v / v). Subsequently, concentrated hydrochloric acid (500 μl) was added to a methanol (1 ml) solution of this white solid at room temperature, and the mixture was stirred for 25 hours. A 1N aqueous sodium hydroxide solution was added to the reaction mixture at 0 ° C., and the mixture was extracted with chloroform. The combined organic layers were dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated under reduced pressure to obtain 41 mg (28%) of the title compound as a white solid.
MS (ESI) m / z: 258 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.25 (3H, s), 3.90 (2H, brs), 4.04 (3H, s), 7.30-7.35 (1H, m), 7.78-7.83 (1H, m), 8.72-8.75 (1H, m).

[Reference Example 81]
3-Bromo-4-fluoro-2-methoxy-6-methyl-5- (pyridin-2-yl) benzonitrile (I-81)
Under a nitrogen atmosphere, tert-butyl nitrite (324 μl, 2.72 mmol) was added to a suspension of copper bromide (668 mg, 2.99 mmol) in acetonitrile (8 ml), and then 3-amino-4- at 60 ° C. A suspension of fluoro-2-methoxy-6-methyl-5- (pyridin-2-yl) benzonitrile (I-80) (350 mg, 1.36 mmol) in acetonitrile (6 ml) was added dropwise, and the mixture was stirred at the same temperature. Stir for 5 hours. After cooling, 28% aqueous ammonia (6 ml) was added and stirred at room temperature, and the mixture was extracted with ethyl acetate. Next, the combined organic layers were dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 284 mg (65%) of the title compound was obtained as a white solid from a fraction eluted with n-hexane-ethyl acetate (1: 1, v / v).
MS (ESI) m / z: 321, 323 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 2.35 (3H, s), 4.11 (3H, s), 7.32-7.39 (2H, m), 7.81-7.86 (1H M), 8.73-8.76 (1H, m).
IR (ATR): 2233, 1587, 1462, 1402, 1333, 1082 cm ⁻¹ .

[Reference Example 82]
4-Fluoro-3- (2-fluoropyridin-3-yl) -2-methoxy-6-methyl-5- (pyridin-2-yl) benzonitrile (I-82)
Under a nitrogen atmosphere, 3-bromo-4-fluoro-2-methoxy-6-methyl-5- (pyridin-2-yl) benzonitrile (I-81) (273 mg, 850 μmol), 2-fluoro-3- (4 , 4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) pyridine (284 mg, 1.28 mmol), cesium carbonate (554 mg, 1.70 mmol) and tetrakis (triphenylphosphine) palladium (0 ) (98 mg, 85 μmol) in toluene (4 ml) was heated to reflux for 19 hours. After cooling, the reaction solution was diluted with ethyl acetate, filtered, and the filtrate was washed with water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 142 mg (74%) of the title compound was obtained as a pale yellow oil from a fraction eluted with n-hexane-ethyl acetate (1: 1, v / v).
MS (ESI) m / z: 338 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.44 (3H, s), 3.85 (3H, s), 7.28-7.33 (1H, m), 7.34-7.40 (2H M), 7.78-7.85 (2H, m), 8.30-8.33 (1H, m), 8.74-8.77 (1H, m).
IR (ATR): 2227, 1587, 1568, 1439, 1400, 1250 cm ⁻¹ .

[Reference Example 83]
5-Fluoro-7-methyl-6- (pyridin-2-yl) [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-83)
Under a nitrogen atmosphere, 4-fluoro-3- (2-fluoropyridin-3-yl) -2-methoxy-6-methyl-5- (pyridin-2-yl) benzonitrile (I-82) (137 mg, 406 μmol) A solution of triethylamine (170 μl, 1.22 mmol) in dimethyl sulfoxide (8 ml) was stirred at 120 ° C. for 15 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform. Next, the organic layer was washed with water, and then the aqueous layer was extracted with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 76 mg (62%) of the title compound was obtained as a white solid from a fraction eluted with n-hexane-ethyl acetate (1: 1, v / v).
MS (ESI) m / z: 304 (M + 1) ^<+> .

[Example 17]
5-[(3S) -3- (Dimethylamino) pyrrolidin-1-yl] -7-methyl-6- (pyridin-2-yl) [1] benzofuro [2,3-b] pyridine-8-carbonitrile (# 17)
Under a nitrogen atmosphere, 5-fluoro-7-methyl-6- (pyridin-2-yl) [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-83) (76 mg, 251 μmol), triethylamine A solution of (105 μl, 753 μmol) and (3S) -3- (dimethylamino) pyrrolidine (64 μl, 501 μmol) in dimethyl sulfoxide (3 ml) was stirred at 90 ° C. for 18 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform. Next, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, and then the aqueous layer was extracted with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain a crude title compound from an eluate of dichloromethane-methanol (9: 1, v / v), and suspended and washed with diisopropyl ether to give 54 mg (54 mg) of the title compound. %) As a light brown solid.

mp: 204-207 ° C.
MS (ESI) m / z: 398 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 1.68-1.77 (1H, m), 2.02-2.17 (1H, m), 2.15 (6H, s), 2.32 (3H , S), 2.58-2.75 (1H, m), 2.97-3.17 (4H, m), 7.27-7.35 (1H, m), 7.35-7.44. (2H, m), 7.84 (1H, t, J = 7.6 Hz), 8.09 (1H, d, J = 7.6 Hz), 8.46-8.49 (1H, m), 8 .76-8.79 (1H, m).
IR (ATR): 2224, 1583, 1460, 1390, 1362, 1155 cm ⁻¹ .
Anal. _{Calcd for C 24 H 23 N 5} O · 0.25H 2 O: C, 71.71; H, 5.89; N, 17.42. Found: C, 71.82; H, 5.73; N, 17.29.

[Reference Example 84]
3-Amino-4-fluoro-2-methoxy-6-methyl-5- (pyridin-3-yl) benzonitrile (I-84)
Under a nitrogen atmosphere, 3-amino-5-bromo-4-fluoro-2-methoxy-6-methylbenzonitrile (I-73) (1.00 g, 3.86 mmol), pyridine-3-boronic acid (569 mg, 4 .63 mmol), tripotassium phosphate (1.64 g, 7.72 mmol) and tetrakis (triphenylphosphine) palladium (0) (446 mg, 386 μmol) in 1,4-dioxane (19 ml) were heated for 62 hours. Refluxed. After cooling, the reaction solution was diluted with ethyl acetate, filtered, and the filtrate was washed with water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 483 mg (49%) of the title compound was obtained as a brown solid from a fraction eluted with n-hexane-ethyl acetate (1: 1, v / v).
MS (ESI) m / z: 258 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.24 (3H, s), 3.94 (2H, brs), 4.07 (3H, s), 7.38-7.43 (1H, m), 7.55-7.60 (1H, m), 8.49-8.51 (1H, m), 8.66 (1H, dd, J = 4.9, 1.7 Hz).
IR (ATR): 3444, 3311, 3182, 2222, 1631, 1481, 1408, 1296, 1161, 1063 cm ⁻¹ .

[Reference Example 85]
3-Bromo-4-fluoro-2-methoxy-6-methyl-5- (pyridin-3-yl) benzonitrile (I-85)
Under a nitrogen atmosphere, tert-butyl nitrite (438 μl, 3.68 mmol) was added to a suspension of copper bromide (904 mg, 4.05 mmol) in acetonitrile (12 ml), and then 3-amino-4 at 60 ° C. A suspension of -fluoro-2-methoxy-6-methyl-5- (pyridin-3-yl) benzonitrile (474 mg, 1.84 mmol) in acetonitrile (6 ml) was added dropwise and stirred at the same temperature for 5 hours. After cooling, the reaction mixture was diluted with ethyl acetate, and water and saturated brine were added. Next, the precipitated solid was collected by filtration, then this solid was dissolved in a tetrahydrofuran-water (5 ml-5 ml) mixed solvent, potassium iodide (611 mg, 3.68 mmol) was added, and the mixture was stirred at room temperature for 93 hours. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water and saturated brine. The insoluble material was removed by filtration, and the filtrate was washed with saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 203 mg (34%) of the title compound was obtained as an orange solid from a fraction eluted with ethyl acetate.
MS (ESI) m / z: 321, 323 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 2.34 (3H, s), 4.13 (3H, s), 7.44 (1H, dd, J = 7.8, 4.9 Hz), 7.56 −7.60 (1H, m), 8.50 (1H, brs), 8.71 (1H, d, J = 4.2 Hz).
IR (ATR): 2231, 1396, 1335, 1147, 1078 cm ⁻¹ .

[Reference Example 86]
4-Fluoro-3- (2-fluoropyridin-3-yl) -2-methoxy-6-methyl-5- (pyridin-3-yl) benzonitrile (I-86)
Under a nitrogen atmosphere, 3-bromo-4-fluoro-2-methoxy-6-methyl-5- (pyridin-3-yl) benzonitrile (I-85) (96 mg, 299 μmol), 2-fluoro-3- (4 , 4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) pyridine (100 mg, 448 μmol), cesium carbonate (195 mg, 598 μmol) and tetrakis (triphenylphosphine) palladium (0) (35 mg, A suspension of 30 μmol) in toluene (1.5 ml) was heated to reflux for 18 hours. After cooling, the reaction solution was diluted with ethyl acetate, filtered, and the filtrate was washed with water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 75 mg (74%) of the title compound was obtained as a pale yellow oil from a fraction eluted with n-hexane-ethyl acetate (1: 2, v / v).
MS (ESI) m / z: 338 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.43 (3H, s), 3.87 (3H, s), 7.31-7.35 (1H, m), 7.41-7.50 (1H M), 7.61-7.66 (1H, m), 7.80-7.86 (1H, m), 8.31-8.35 (1H, m), 8.55 (1H, brs) ), 8.68-8.71 (1H, m).

[Example 18]
5-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -7-methyl-6- (pyridin-3-yl) [1] benzofuro [2,3-b] pyridine-8-carbonitrile (# 18)

  Under a nitrogen atmosphere, 4-fluoro-3- (2-fluoropyridin-3-yl) -2-methoxy-6-methyl-5- (pyridin-3-yl) benzonitrile (I-86) (138 mg, 409 μmol) And triethylamine (138 μl, 1.23 mmol) in dimethyl sulfoxide (4 ml) were stirred at 130 ° C. for 4.5 hours, and (3S) -3- (dimethylamino) pyrrolidine (104 μl, 818 μmol) was added at the same temperature. After the addition, the mixture was further stirred for 13.5 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform. Next, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, and then the aqueous layer was extracted with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give the crude title compound from the eluate of dichloromethane-methanol (10: 1, v / v), and suspended and washed with diethyl ether to give 36 mg (22%) of the title compound. ) Was obtained as a light brown solid.

mp: 194-196 ° C.
MS (ESI) m / z: 398 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 1.75-2.00 (1H, m), 2.02-2.30 (7H, m), 2.36 (3H, s), 2.80-3 .20 (5H, m), 7.41-7.50 (2H, m), 7.53-7.62 (1H, m), 8.12-8.25 (1H, m), 8.47 -8.53 (2H, m), 8.70-8.73 (1H, m).
IR (ATR): 2222, 1587, 1566, 1464, 1390, 1363, 1211, 1165 cm ⁻¹ .
Anal. _{Calcd for C 24 H 23 N 5} O · 1.25H 2 O: C, 68.63; H, 6.12; N, 16.67. Found: C, 68.93; H, 5.78; N, 16.43.

[Reference Example 87]
3-Amino-4-fluoro-2-methoxy-6-methyl-5- (pyridin-4-yl) benzonitrile (I-87)
Under nitrogen atmosphere, 3-amino-5-bromo-4-fluoro-2-methoxy-6-methylbenzonitrile (I-73) (554 mg, 2.14 mmol), pyridine-4-boronic acid (399 mg, 3.25 mmol) ), Tripotassium phosphate (909 mg, 4.28 mmol) and tetrakis (triphenylphosphine) palladium (0) (247 mg, 214 μmol) in 1,4-dioxane (11 ml) were heated to reflux for 88 hours. After cooling, the reaction solution was diluted with ethyl acetate, filtered, and the filtrate was washed with water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 204 mg (37%) of the title compound was obtained as a light brown solid from a fraction eluted with n-hexane-ethyl acetate (1: 1, v / v).
MS (ESI) m / z: 258 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.23 (3H, s), 3.95 (2H, brs), 4.07 (3H, s), 7.19 (2H, brs), 8.76 ( 2H, brs).
IR (ATR): 3406, 3313, 3197, 2233, 1643, 1597, 1477, 1406, 1360, 1294, 1203 cm ⁻¹ .

[Reference Example 88]
3-Bromo-4-fluoro-2-methoxy-6-methyl-5- (pyridin-4-yl) benzonitrile (I-88)
Under a nitrogen atmosphere, tert-butyl nitrite (370 μl, 3.11 mmol) was added to a suspension of copper bromide (762 mg, 3.41 mmol) in acetonitrile (10 ml), and then 3-amino-4- at 60 ° C. A suspension of fluoro-2-methoxy-6-methyl-5- (pyridin-4-yl) benzonitrile (I-87) (400 mg, 1.55 mmol) in acetonitrile (6 ml) was added dropwise, and 5 ° C. at the same temperature. Stir for hours. After cooling, 28% aqueous ammonia (6 ml) was added and stirred at room temperature, and the mixture was extracted with ethyl acetate. Next, the combined organic layers were dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was suspended and washed with diisopropyl ether to give 273 mg (55%) of the title compound as a light brown solid.
MS (ESI) m / z: 321, 323 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 2.32 (3H, s), 4.13 (3H, s), 7.20-7.35 (4H, m).
IR (ATR): 2227, 1595, 1462, 1412, 1336, 1080 cm ⁻¹ .

[Reference Example 89]
4-Fluoro-3- (2-fluoropyridin-3-yl) -2-methoxy-6-methyl-5- (pyridin-4-yl) benzonitrile (I-89)
Under a nitrogen atmosphere, 3-bromo-4-fluoro-2-methoxy-6-methyl-5- (pyridin-4-yl) benzonitrile (I-88) (270 mg, 841 μmol), 2-fluoro-3- (4 , 4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) pyridine (281 mg, 1.26 mmol), cesium carbonate (548 mg, 1.68 mmol) and tetrakis (triphenylphosphine) palladium (0 ) (97 mg, 84 μmol) in toluene (4 ml) was heated to reflux for 18.5 hours. After cooling, the reaction solution was diluted with ethyl acetate, filtered, and the filtrate was washed with water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 143 mg (50%) of the title compound was obtained as a pale yellow oil from a fraction eluted with n-hexane-ethyl acetate (1: 2, v / v).
MS (ESI) m / z: 338 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.42 (3H, s), 3.87 (3H, s), 7.22-7.24 (2H, m), 7.31-7.35 (1H M), 7.79-7.85 (1H, m), 8.31-8.34 (1H, m), 8.75 (2H, d, J = 6.1 Hz).
IR (ATR): 2227, 1601, 1568, 1439, 1404, 1080 cm ⁻¹ .

[Example 19]
5-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -7-methyl-6- (pyridin-4-yl) [1] benzofuro [2,3-b] pyridine-8-carbonitrile (# 19)
Under a nitrogen atmosphere, 4-fluoro-3- (2-fluoropyridin-3-yl) -2-methoxy-6-methyl-5- (pyridin-4-yl) benzonitrile (I-89) (133 mg, 394 μmol) And triethylamine (133 μl, 954 μmol) in dimethyl sulfoxide (4 ml) were stirred at 130 ° C. for 19.5 hours, and (3S) -3- (dimethylamino) pyrrolidine (100 μl, 788 μmol) was added at the same temperature. Thereafter, the mixture was further stirred for 23 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform. Next, the organic layer was washed with saturated aqueous sodium hydrogen carbonate, and the aqueous layer was extracted with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain a crude title compound from an eluate of dichloromethane-methanol (10: 1, v / v), and 20 mg (13% of the title compound) was suspended and washed with diisopropyl ether. ) Was obtained as a light brown solid.

mp: 267-270 ° C.
MS (ESI) m / z: 398 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 1.73-1.86 (1H, m), 2.05-2.13 (1H, m), 2.19 (6H, s), 2.34 (3H , S), 2.61-2.71 (1H, m), 2.91-3.17 (4H, m), 7.16-7.23 (2H, m), 7.41-7.46. (1H, m), 8.13-8.18 (1H, m), 8.50 (1H, d, J = 4.9 Hz), 8.76 (2H, d, J = 5.1 Hz).
IR (ATR): 2224, 1597, 1466, 1389, 1211, 1159 cm ⁻¹ .
Anal. _{Calcd for C 24 H 23 N 5} O · 0.75H 2 O: C, 70.14; H, 6.01; N, 17.04. Found: C, 70.40; H, 5.79; N, 16.58.

[Reference Example 90]
5-Amino-6-fluoro-4-methoxy-2-methylbiphenyl-3-carbonitrile (I-90)
5-amino-2-bromo-6-fluoro-4-methoxybiphenyl-3-carbonitrile (I-61) (2.02 g, 6.29 mmol), potassium carbonate (2.61 g, 18.87 mmol), tetrakis ( Triphenylphosphine) palladium (0) (727 mg, 0.63 mmol) was dissolved in 1,4-dioxane (50 ml) containing 10% water, and trimethylboroxine (50 wt% tetrahydrofuran solution; 1.90 ml, 7.55 mmol) at room temperature. ) Was added. After stirring at 110 ° C. for 8 hours under a nitrogen stream, the mixture was cooled to room temperature, tetrakis (triphenylphosphine) palladium (0) (727 mg, 0.63 mmol) was added, and the mixture was further stirred at 110 ° C. for 11 hours. After cooling to room temperature, insoluble matters were filtered off, and the filtrate was fractionated with ethyl acetate and saturated brine. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After separation by filtration, the residue obtained by distilling off the solvent was dissolved in a small amount of chloroform, silica gel was added, and then excess solvent was distilled off. This powder was purified by column chromatography using silica gel (eluent; n-hexane: ethyl acetate = 4: 1, v / v) to obtain 1.567 g (97%) of the title compound as a light brown solid. .
MS (EI) m / z: 256 (M ^<+> ).
HRMS (EI) m / z: 256.1014 (Calcd for C 15 H 13 FN 2 O 256.1012).
¹ H-NMR (CDCl ₃ ) δ: 2.22 (3H, s), 3.88 (2H, br s), 4.05 (3H, s), 7.18-7.23 (2H, m) , 7.38-7.48 (3H, m).
IR (ATR): 3367, 2224, 1477, 1431, 1358, 1296, 1151, 1059, 939, 775, 711 cm ⁻¹ .

[Reference Example 91]
5-Bromo-6-fluoro-4-methoxy-2-methylbiphenyl-3-carbonitrile (I-91)
Copper (II) bromide (1.54 g, 6.87 mmol) was dissolved in acetonitrile (15 ml), and tert-butyl nitrite (purity 90%, 825 μl, 6.24 mmol) was added at room temperature under a nitrogen stream. After the solution was stirred at 60 ° C. for 10 minutes, 5-amino-6-fluoro-4-methoxy-2-methylbiphenyl-3-carbonitrile (I-90) (800 mg, 3.12 mmol) was added to acetonitrile (16 ml). ) Was slowly added to the solution. After stirring at the same temperature for 1 hour, it was cooled to room temperature. The reaction mixture was fractionated with ethyl acetate and 1N aqueous hydrochloric acid. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 9: 1, v / v), and 828 mg (83%) of the title compound was white. Obtained as a solid.
MS (ESI) m / z: 320, 322 (M + 1) ⁺ .
HRMS (EI) m / z: 319.0023 (Calcd for C ₁₅ H ₁₁ ⁷⁹ BrFNO 319.0008), 321.0012 (Calcd for C ₁₅ H ₁₁ ⁸¹ BrFNO 320.99988).
¹ H-NMR (CDCl ₃ ) δ: 2.31 (3H, s), 4.11 (3H, s), 7.19-7.22 (2H, m), 7.41-7.50 (3H , M).
IR (ATR): 2227, 1412, 1336, 1082, 943, 752, 702 cm ⁻¹ .

[Reference Example 92]
6-Fluoro-5- (2-fluoropyridin-3-yl) -4-methoxy-2-methylbiphenyl-3-carbonitrile (I-92)
5-Bromo-6-fluoro-4-methoxy-2-methylbiphenyl-3-carbonitrile (I-91) (828 mg, 2.586 mmol), 2-fluoro-3- (4,4,5,5-tetra Methyl [1,3,2] dioxaboran-2-yl) pyridine (1.154 g, 5.17 mmol) and cesium carbonate (1.685 g, 5.17 mmol) were suspended in toluene (17 ml) and brought to room temperature under a nitrogen stream. Tetrakis (triphenylphosphine) palladium (0) (448 mg, 0.39 mmol) was added. The suspension was heated to reflux for 12 hours and then cooled to room temperature. The insoluble material was filtered off while washing with ethyl acetate, and the filtrate was fractionated with ethyl acetate and saturated brine. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After separation by filtration, the residue obtained by evaporating the solvent was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 4: 1, v / v), and 606 mg (70 %) As a colorless gel.
MS (ESI) m / z: 337 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.40 (3H, s), 3.84 (3H, s), 7.23-7.30 (2H, m), 7.31 (1H, ddd, J = 1.7, 4.9, 7.3 Hz), 7.40-7.50 (3H, m), 7.83 (1H, ddd, J = 1.7, 7.3, 9.0 Hz) , 8.30-8.33 (1H, m).

[Reference Example 93]
5-Fluoro-7-methyl-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-93)
6-Fluoro-5- (2-fluoropyridin-3-yl) -4-methoxy-2-methylbiphenyl-3-carbonitrile (I-92) (605 mg, 1.80 mmol) dissolved in dimethyl sulfoxide (12 ml) Then, triethylamine (752 μl, 5.40 mmol) was added at room temperature under a nitrogen stream. The temperature was gradually raised from room temperature to 120 ° C., and the mixture was stirred at the same temperature for 11.5 hours. After cooling to room temperature, the reaction mixture was fractionated with ethyl acetate and saturated brine. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified using medium pressure liquid chromatography (eluent: n-hexane: ethyl acetate = 4: 1, v / v), and 415 mg (76%) of the title compound was white. Obtained as a solid.
MS (ESI) m / z: 303 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.51 (3H, s), 7.27-7.32 (2H, m), 7.44 (1H, dd, J = 4.9, 7.6 Hz) 7.47-7.56 (3H, m), 8.33 (1H, dd, J = 1.7, 7.6 Hz), 8.55 (1H, dd, J = 1.7, 4.9 Hz) ).

[Example 20]
5-[(3S) -3- (Methylamino) pyrrolidin-1-yl] -7-methyl-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile hydrochloride (# 20)

  Under a nitrogen atmosphere, 5-fluoro-7-methyl-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-93) (300 mg, 0.99 mmol) was added to dimethyl sulfoxide (6 ml). Triethylamine (349 μl, 2.48 mmol) and (3S) -3- (methylamino) pyrrolidine (137 μl, 1.29 mmol) were added, and the mixture was stirred at 90 ° C. for 14 hours. After cooling to room temperature, chloroform was added, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was subjected to silica gel chromatography and eluted with a mixed solvent of chloroform-methanol (40: 1, v / v) to obtain 263 mg of the main product as a yellowish white solid. This was dissolved in a mixed solution of ethanol (10 ml) and chloroform (5 ml), 1N hydrochloric acid (ethanol solution) (756 μl, 0.756 mmol) was added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and recrystallized from chloroform-diisopropyl ether-ethanol to obtain 286 mg (64%) of the title compound as a white solid.

mp: 283-284 ° C. (dec.)
MS (FAB) m / z: 383 (M + 1) ^<+> .
¹ H-NMR (DMSO-d ₆ ) δ: 1.91-2.00 (1H, m), 2.25 (3H, s), 2.17-2.24 (1H, m), 2.44 (3H, s), 2.91 (1H, dd, J = 6.7, 10.4 Hz), 3.01-3.07 (1H, m), 3.14-3.22 (3H, m) 3.58-3.65 (1H, m), 7.30 (2H, t, J = 7.7 Hz), 7.46-7.59 (4H, m), 8.29 (1H, dd, J = 1.6, 7.9 Hz), 8.51 (1H, dd, J = 1.3, 4.8 Hz).
IR (ATR): 2224, 1593, 1464, 1390 cm ⁻¹ .
Anal. _{Calcd for C 24 H 22 N 4} O · 1.75H 2 O · HCl: C, 63.99; H, 5.93; N, 12.44; Cl, 7.87. Found: C, 64.12; H, 5.66; N, 12.15, Cl, 8.50.

[Example 21]
5-[(3S, 4S) -3-Ethyl-4- (methylamino) pyrrolidin-1-yl] -7-methyl-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (# 21)
Under a nitrogen atmosphere, 5-fluoro-7-methyl-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-93) (250 mg, 0.83 mmol) was added to dimethyl sulfoxide (5 ml). Triethylamine (291 μl, 2.07 mmol) and tert-butyl (3S, 4S) -4-ethylpyrrolidinyl (methyl) carbamate (245 mg, 1.08 mmol) were added and stirred at 90 ° C. for 15 hours. Furthermore, it stirred at 110 degreeC for 26 hours. After cooling to room temperature, water was added, and the mixture was suspended in ethyl acetate and extracted with excess chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was subjected to preparative thin-layer chromatography and eluted with a mixed solvent of n-hexane-ethyl acetate (1: 1, v / v) to obtain a main product. . This was dissolved in 1,4-dioxane solution (6 ml) of 4N hydrochloric acid and stirred at room temperature for 7 hours. N-Hexane was added to the reaction solution, followed by extraction with water. The obtained aqueous layer was made basic with a 1N aqueous sodium hydroxide solution and re-extracted with chloroform. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was recrystallized from chloroform-ethyl acetate-diisopropyl ether to obtain 180 mg (52%) of the title compound as a light brown solid.

mp: 232-234 ° C. (dec.)
MS (ESI) m / z: 411 (M + 1) ⁺ .
¹ H-NMR (DMSO-d ₆ ) δ: 0.76 (3H, t, J = 7.4 Hz), 1.11-1.19 (1H, m), 1.41-1.48 (1H, m), 1.95 (1H, br s), 2.20 (3H, s), 2.25 (3H, s), 2.81 (2H, dd, J = 8.3, 8.8 Hz), 2.87 (2H, dd, J = 5.4, 11.5 Hz), 2.99-3.13 (3H, m), 7.27 (2H, d, J = 6.6 Hz), 7.43 -7.58 (4H, m), 8.32 (1H, dd, J = 1.5, 7.6 Hz), 8.46 (1H, dd, J = 1.7, 4.9 Hz).
IR (ATR): 2218, 1589, 1392 cm ⁻¹ .
Anal. _{Calcd for C 26 H 26 N 4} O · 0.5H 2 O: C, 74.44; H, 6.49; N, 13.35. Found: C, 74.55; H, 6.26; N, 13.08.

[Reference Example 94]
7-Bromomethyl-5-fluoro-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-94)
5-Fluoro-7-methyl-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-93) (300 mg, 0.99 mmol) was added to carbon tetrachloride (6 ml) and benzene ( 6 ml), and N-bromosuccinimide (265 mg, 1.49 mmol) and azobisisobutyronitrile (16 mg, 0.1 mmol) were added to this solution at room temperature. The mixture was stirred at 85 ° C. for 3 hours under a nitrogen stream and then cooled to room temperature. The reaction solution was fractionated with chloroform and saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was separated and extracted with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 4: 1, v / v) to give the title compound. 366 mg (97%) were obtained as a white solid.
MS (ESI) m / z: 381, 383 (M + 1) ⁺ .
HRMS (EI) m / z: 379.9944 (Calcd for C ₁₉ H ₁₀ ⁷⁹ BrFN ₂ O 379.9961), 381.9910 (Calcd for C ₁₉ H ₁₀ ⁸¹ BrFN ₂ O 381.9940)
¹ H-NMR (CDCl ₃ ) δ: 4.57 (2H, s), 7.43-7.51 (3H, m), 7.52-7.60 (3H, m), 8.38 (1H , Dd, J = 1.7, 7.6 Hz), 8.59 (1H, dd, J = 1.7, 5.1 Hz).
IR (ATR): 2229, 1589, 1389, 1315, 1296, 1109, 1049, 839, 802, 771, 760, 702 cm ⁻¹ .

[Reference Example 95]
5-Methoxy-7-methoxymethyl-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-95)
7-Bromomethyl-5-fluoro-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-94) (429 mg, 1.13 mmol) was added to N, N-dimethylformamide (4 ml). And dissolved in methanol (8 ml), and potassium carbonate (311 mg, 2.25 mmol) was added at room temperature. The suspension was stirred at 70 ° C. for 5.5 hours. After cooling to room temperature, the organic solvent was distilled off under reduced pressure. The residue was fractionated with ethyl acetate and saturated brine. The aqueous layer was separated and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 4: 1, v / v) to give the title compound. 280 mg (72%) was obtained as a white solid.
MS (ESI) m / z: 345 (M + 1) ^<+> .
HRMS (EI) m / z: 344.1144 (Calcd for C 21 H 16 N 2 O 3 344.1161).
¹ H-NMR (CDCl ₃ ) δ: 3.34 (3H, s), 3.62 (3H, s), 4.38 (2H, s), 7.40-7.44 (3H, m), 7.47-7.54 (3H, m), 8.38 (1H, dd, J = 1.7, 7.6Hz), 8.49 (1H, dd, J = 1.7, 4.9Hz) .
IR (ATR): 2227, 1581, 1379, 1298, 1093, 1061, 773, 723, 704 cm ⁻¹ .

[Reference Example 96]
8-cyano-7-methoxymethyl-6-phenyl [1] benzofuro [2,3-b] pyridin-5-yl trifluoromethanesulfonate (I-96)
5-methoxy-7-methoxymethyl-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-95) (280 mg, 0.81 mmol), sodium acetate (200 mg, 2.44 mmol) ) Was dissolved in N, N-dimethylacetamide (5.6 ml) and stirred at 130 ° C. for 17 hours. After cooling this reaction liquid to room temperature, the solvent was distilled off under reduced pressure. The residue was fractionated with chloroform containing 5% methanol and 1N aqueous hydrochloric acid. The aqueous layer was separated and extracted with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off and the solvent was distilled off to obtain a light brown solid. This was dried under reduced pressure and dissolved in pyridine (5.4 ml). 4- (Dimethylamino) pyridine (20 mg, 0.16 mmol) and trifluoromethanesulfonic anhydride (412 μl, 2.44 mmol) were added at room temperature, and the mixture was stirred at room temperature for 24 hours under a nitrogen stream. The solvent was distilled off under reduced pressure, and the resulting residue was fractionated with ethyl acetate and 1N aqueous hydrochloric acid. The aqueous layer was separated and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 4: 1, v / v) to give the title compound. 332 mg (88%) was obtained as a white solid.
HRMS (EI) m / z: 462.0491 (Calcd for C 21 H 13 FN 2 O 5 S 462.0498).
¹ H-NMR (CDCl ₃ ) δ: 3.36 (3H, s), 4.43 (2H, s), 7.38-7.41 (2H, m), 7.49-7.55 (4H M), 8.63 (1H, s), 8.65 (1H, q, J = 1.7 Hz).
IR (ATR): 2237, 1593, 1396, 1215, 1126, 1099, 987, 816 cm ⁻¹ .

[Reference Example 97]
tert-Butyl [3- (8-cyano-7-methoxymethyl-6-phenyl [1] benzofuro [2,3-b] pyridin-5-yl) cyclopent-2-en-1-yl] carbamate (I- 97)
8-cyano-7-methoxymethyl-6-phenyl [1] benzofuro [2,3-b] pyridin-5-yl trifluoromethanesulfonate (I-96) (331 mg, 0.72 mmol), tert-butyl (3- Tri n-butylstannylcyclopent-2-en-1-yl) carbamate (507 mg, 1.07 mmol) was dissolved in 1,4-dioxane (6.6 ml), and lithium chloride (91 mg, 2.15 mmol) at room temperature. ), 2,6-ditert-butyl-p-cresol (3.2 mg, 0.02 mmol), dichlorobis (triphenylphosphine) palladium (II) (75 mg, 0.11 mmol). The mixture was stirred at 110 ° C. for 24 hours under a nitrogen stream and then cooled to room temperature. The insoluble material was filtered off while washing with ethyl acetate. The filtrate was washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (6.6 ml), water (193 μl, 10.74 mmol) and potassium fluoride (312 mg, 5.37 mmol) were added, and the mixture was vigorously stirred at room temperature for 8 hours. The insoluble material was filtered off while washing with dichloromethane, and the filtrate was washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered off and the solvent was distilled off under reduced pressure. The residue was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 3: 1, v / v) to obtain 294 mg (83%) of the title compound as a white solid.
MS (ESI) m / z: 496 (M + 1) ⁺ .
HRMS (FAB) m / z: 496.2218 (Calcd for C 30 H 30 N 3 O 4 496.2236).
¹ H-NMR (CDCl ₃ ) δ: 1.23-1.40 (2H, m), 1.46 (9H, s), 1.55-1.68 (1H, m), 2.20-2 .40 (2H, m), 3.32 (3H, s), 4.41 (2H, s), 4.66-4.86 (1H, br), 5.69 (1H, br s), 7 .23-7.28 (2H, m), 7.36 (1H, dd, J = 4.9, 7.8 Hz), 7.40-7.48 (3H, m), 8.03-8. 16 (1H, br), 8.52 (1H, dd, J = 1.7, 4.9 Hz).
IR (ATR): 2229, 1709, 1495, 1390, 1165, 1097, 754, 704 cm ⁻¹ .

[Example 22]
5- (3-Dimethylaminocyclopent-1-en-1-yl) -7-methoxymethyl-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (# 22)
tert-Butyl [3- (8-cyano-7-methoxymethyl-6-phenyl [1] benzofuro [2,3-b] pyridin-5-yl) cyclopent-2-en-1-yl] carbamate (I- 97) (290 mg, 0.59 mmol) was dissolved in 1,4-dioxane solution (5.8 ml) of 4N hydrochloric acid and stirred at room temperature for 3 hours. Tetrahydrofuran was added to the residue obtained by distilling off the solvent under reduced pressure, followed by azeotropic distillation. This operation was repeated twice more. Chloroform and 1N aqueous sodium hydroxide solution were added to the residue, and the mixture was vigorously stirred for 30 minutes. The aqueous layer was separated and extracted with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by distilling off the solvent was dried under reduced pressure and used in the next reaction without purification. Methanol (6 ml) was added to the light brown solid, and a 37% formaldehyde solution (285 μl, 3.51 mmol), acetic acid (209 μl, 3.51 mmol), sodium cyanoborohydride ( 132 mg, 2.11 mmol) was added. The temperature was gradually raised from 0 ° C. to room temperature, and the mixture was stirred at the same temperature for 12 hours. Chloroform and 1N aqueous sodium hydroxide solution were added to the reaction solution, and the mixture was vigorously stirred at room temperature for 20 minutes. The aqueous layer was separated and extracted with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using preparative TLC (eluent; chloroform: methanol = 85: 15, v / v) to give 147 mg (59%) of the title compound. Was obtained as a white solid.

MS (ESI) m / z: 424 (M + 1) ^<+> .
HRMS (EI) m / z: 423.1968 (Calcd for C 27 H 25 N 3 O 2 423.1947).
¹ H-NMR (CDCl ₃ ) δ: 1.70-2.75 (10H, m), 3.30 (3H, s), 3.45-4.45 (1H, br), 4.35 (1H , D, J = 10.3 Hz), 4.39 (1H, d, J = 10.3 Hz), 5.79 (1H, d, J = 2.0 Hz), 7.21-7.28 (2H, m), 7.34-7.43 (4H, m), 8.03-8.23 (1H, br), 8.51 (1H, dd, J = 1.7, 4.9 Hz).
IR (ATR): 2225, 1390, 1379, 1342, 1103, 768, 721 cm ⁻¹ .
Anal. _{Calcd for C 27 H 25 N 3} O 2 · 0.25H 2 O: C, 75.77; H, 6.00; N, 9.82. Found: C, 75.49; H, 5.96; N, 9.32.

[Reference Example 98]
7-acetoxymethyl-5-fluoro-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-98)
7-Bromomethyl-5-fluoro-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-94) (366 mg, 0.96 mmol) was dissolved in acetic acid (7.3 ml). Then, anhydrous sodium acetate (788 mg, 960 mmol) was added at room temperature, and the mixture was stirred at 100 ° C. for 9 hours under a nitrogen stream. After cooling to room temperature, the solvent was distilled off under reduced pressure. The residue was fractionated with ethyl acetate and saturated brine. The aqueous layer was separated and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 3: 1, v / v) to give the title compound. 302 mg (87%) were obtained as a white solid.
MS (ESI) m / z: 361 (M + 1) ⁺ .
HRMS (EI) m / z: 360.0903 (Calcd for C 21 H 13 FN 2 O 3 360.0910).
¹ H-NMR (CDCl ₃ ) δ: 2.06 (3H, s), 5.17 (2H, s), 7.31-7.35 (2H, m), 7.49 (1H, dd, J = 4.9, 7.6 Hz), 7.49-7.55 (3H, m), 8.40 (1 H, dd, J = 1.7, 7.6 Hz), 8.61 (1 H, dd, J = 1.7, 4.9 Hz).
IR (ATR): 2231, 1741, 1392, 1211, 1111, 1026, 864, 721, 702 cm ⁻¹ .

[Example 23]
7-acetoxymethyl-5-[(3S) -3-dimethylaminopyrrolidin-1-yl] -6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (# 23)
7-acetoxymethyl-5-fluoro-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-98) (296 mg, 082 mmol) was dissolved in dimethyl sulfoxide (6 ml) at room temperature. Triethylamine (229 μl, 1.64 mmol) and (3S) -3- (dimethylamino) pyrrolidine (136 μl, 1.07 mmol) were added. The suspension was stirred at 100 ° C. for 10 hours and then cooled to room temperature. The reaction mixture was fractionated with ethyl acetate and saturated brine. The aqueous layer was separated and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using preparative TLC (chloroform: methanol = 95: 5, v / v) to give 237 mg (64%) of the title compound as a light brown color. Obtained as a solid.

MS (ESI) m / z: 455 (M + 1) ^<+> .
HRMS (EI) m / z: 454.2029 (Calcd for C 27 H 26 N 4 O 3 454.2005).
¹ H-NMR (CDCl ₃ ) δ: 1.74 (1H, dq, J = 8.3, 2.2 Hz), 2.02 (3H, s), 2.03-2.15 (1H, m) 2.15 (6H, s), 2.61 (1H, dq, J = 7.8, 10.0 Hz), 2.78 (1H, dd, J = 7.8, 9.5 Hz), 3. 05 (2H, dd, J = 5.6, 7.8 Hz), 3.09 (1H, dd, J = 7.8, 9.5 Hz), 5.00 and 5.03 (each 1H, each d, J = 12.2 Hz), 7.20-7.27 (2 H, m), 7.43-7.50 (4 H, m), 8.16 (1 H, dd, J = 1.7, 7.6 Hz) ), 8.51 (1H, dd, J = 1.7, 4.9 Hz).
IR (ATR): 2222, 1732, 1398, 1363, 1224, 1153, 1026, 700 cm ⁻¹ .
Anal. _{Calcd for C 27 H 26 N 4} O 3 · 0.25H 2 O: C, 70.65; H, 5.82; N, 12.21. Found: C, 70.55; H, 5.67; N, 12.13.

[Example 24]
(3S) -1- (1-Imino-4-phenyl-1,3-dihydrofuro [3 ′, 4 ′: 6,7] [1] benzofuro [2,3-b] pyridin-5-yl) -N , N-dimethylpyrrolidin-3-amine (# 24)
7-acetoxymethyl-5-[(3S) -3-dimethylaminopyrrolidin-1-yl] -6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (# 23) (131 mg, 0.29 mmol) was dissolved in methanol (2.6 ml), potassium carbonate (120 mg, 0.87 mmol) was added at room temperature, and the mixture was stirred at the same temperature for 3.5 hours. The reaction solution was fractionated with chloroform and saturated brine. The aqueous layer was separated and extracted three times with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue was recrystallized from ethyl acetate to obtain 87 mg (73%) of the title compound as light brown crystals.

MS (ESI) m / z: 413 (M + 1) ^<+> .
HRMS (EI) m / z: 412.1899 (Calcd for C 25 H 24 N 4 O 2 412.1899).
¹ H-NMR (CDCl ₃ ) δ: 1.78 (1H, dq, J = 8.3, 12.0 Hz), 2.08-2.20 (1H, m), 2.16 (6H, s) , 2.68 (1H, quint, J = 7.6 Hz), 2.93 (1H, t, J = 8.3 Hz), 3.12-3.26 (3H, m), 5.08 (2H, s), 7.28-7.30 (2H, m), 7.42-7.51 (4H, m), 8.18 (1H, dd, J = 1.5, 7.6 Hz), 8. 50 (1H, dd, J = 1.5, 4.9 Hz).
IR (ATR): 1662, 1456, 1389, 1356, 1151, 1043, 966, 910, 808, 777, 719, 704 cm ⁻¹ .
Anal. _{Calcd for C 25 H 24 N 4} O 2 · 1.5H 2 O: C, 68.32; H, 6.19; N, 12.75. Found: C, 68.05; H, 5.40; N, 12.21.

[Example 25]
5-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -4-phenylfuro [3 ′, 4 ′: 6,7] [1] benzofuro [2,3-b] pyridine-1 (3H )-ON (# 25)

  (3S) -1- (1-Imino-4-phenyl-1,3-dihydrofuro [3 ′, 4 ′: 6,7] [1] benzofuro [2,3-b] pyridin-5-yl) -N , N-dimethylpyrrolidin-3-amine (# 24) (20 mg, 0.05 mmol) is dissolved in chloroform, adsorbed on preparative TLC, and mixed with chloroform-methanol (9: 1, v / v). Developed for 1.75 hours. After the development, the plate was left to dry at room temperature for 12 hours. The portion having UV (254 nm) absorption was scraped off, a mixed solution of chloroform-methanol (9: 1, v / v) was added, and the mixture was stirred for 10 minutes. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give 19.6 mg (98%) of the title compound as a white solid.

MS (ESI) m / z: 414 (M + 1) ^<+> .
HRMS (EI) m / z: 413.1750 (Calcd for C 25 H 23 N 3 O 3 413.1740).
¹ H-NMR (CDCl ₃ ) δ: 1.81 (1H, dq, J = 8.3, 12.0 Hz), 2.10-2.20 (1H, m), 2.20 (6H, s) 2.73 (1H, dq, J = 7.6, 7.6 Hz), 2.97 (1H, t, J = 8.3 Hz), 3.15-3.30 (3H, m), 4. 99 (2H, s), 7.33 (2H, d, J = 6.6 Hz), 7.39 (1H, dd, J = 4.9, 7.6 Hz), 7.45-7.55 (3H M), 8.11 (1H, dd, J = 1.7, 7.6 Hz), 8.46 (1H, dd, J = 1.7, 4.9 Hz).
IR (ATR): 1767, 1639, 1587, 1362, 1055, 1028, 1005, 721, 704 cm ⁻¹ .
Anal. _{Calcd for C 25 H 23 N 3} O 3 · 0.25H 2 O: C, 71.84; H, 5.67; N, 10.05. Found: C, 71.48; H, 5.61; N, 9.91.

[Reference Example 99]
5-Methoxy-7-methyl-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-99)
5-Fluoro-7-methyl-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-93) (2.62 g, 8.67 mmol) was suspended in methanol (50 ml). Sodium methoxide (4.2 ml, 18.20 mmol) was added at room temperature. The suspension was heated to reflux for 6 hours and then cooled to room temperature. The solvent was distilled off under reduced pressure, and the resulting residue was fractionated with ethyl acetate, water and saturated brine. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After separation by filtration, the residue obtained by distilling off the solvent under reduced pressure was used for the next reaction without purification.
MS (ESI): 315 (M + 1) ^<+> .

[Reference Example 100]
7-acetoxymethyl-5-methoxy-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-100)
5-Methoxy-7-methyl-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-99) (490 mg, 1.56 mmol) was added to carbon tetrachloride (10 ml) and benzene ( 10-ml) and N-bromosuccinimide (416 mg, 2.34 mmol) and azobisisobutyronitrile (26 mg, 0.16 mmol) were added at room temperature. The mixture was stirred at 85 ° C. for 1 hour and 40 minutes under a nitrogen stream, and then cooled to room temperature. The reaction solution was fractionated with chloroform and saturated brine. The aqueous layer was separated and extracted with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was dissolved in N, N-dimethylformamide (10 ml). To this solution was added sodium acetate (640 mg, 7.80 mmol) at room temperature, and the mixture was stirred at 70 ° C. for 6 hours under a nitrogen stream. After cooling to room temperature, the reaction mixture was fractionated with ethyl acetate and saturated brine. At that time, an insoluble solid in both layers was collected by filtration to obtain 106 mg (18%) of a white solid of the title compound. Meanwhile, the aqueous layer was further extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using medium pressure liquid chromatography (eluent; chloroform: methanol = 98: 2, v / v) to give 164 mg (28 of the title compound) %) As a white solid (total 270 mg, 46%).
MS (ESI) m / z: 373 (M + 1) ^<+> .
HRMS (EI) m / z: 372.1105 (Calcd for C 22 H 16 N 2 O 4 372.1110).
¹ H-NMR (CDCl ₃ ) δ: 2.05 (3H, s), 3.63 (3H, s), 5.11 (2H, s), 7.32-7.35 (2H, m), 7.45 (1H, dd, J = 4.9, 7.6 Hz), 7.47-7.52 (3H, m), 8.40 (1H, dd, J = 1.7 Hz, 7.6 Hz) 8.55 (1H, dd, J = 1.7, 4.9 Hz).
IR (ATR): 2231, 1736, 1296, 1225, 1020, 773, 723 cm ⁻¹ .

[Reference Example 101]
5-Methoxy-4-phenylfuro [3 ′, 4 ′: 6,7] [1] benzofuro [2,3-b] pyridin-1 (3H) -one (I-101)
7-acetoxymethyl-5-methoxy-6-phenyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-100) (485 mg, 1.30 mmol) in methanol (9 ml) and N, N -Dissolved in dimethylformamide (4.5 ml) and added potassium carbonate (540 mg, 3.91 mmol) at room temperature. The solution was heated to 70 ° C. and stirred for 30 minutes. After cooling to room temperature, chloroform (4.5 ml) was added to completely dissolve insoluble matters. After stirring at room temperature for 15 minutes, the mixture was further stirred at 70 ° C. for 1.5 hours. After cooling to room temperature, ethyl acetate and water were added to the reaction solution, and the mixture was vigorously stirred for 10 minutes. The residue obtained by evaporating the solvent under reduced pressure was extracted with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure to give a brown solid. This was dissolved in chloroform (8 ml) and methanol (8 ml), and 1N aqueous hydrochloric acid solution (8 ml) was added at room temperature. After stirring at the same temperature for 15 minutes, concentrated hydrochloric acid (4 ml) was further added and stirred for 4 days. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The residue was dried under reduced pressure to give 386 mg (90%) of the title compound as a brown solid.
MS (ESI) m / z: 332 (M + 1) ^<+> .
HRMS (EI) m / z: 331.0831 (Calcd for C 20 H 13 NO 4 331.0845).
¹ H-NMR (DMSO-d ₆ ) δ: 3.77 (3H, s), 5.43 (2H, s), 7.53-7.68 (6H, m), 8.61 (1H, s) ), 8.63 (1H, q, J = 1.7 Hz).
IR (ATR): 1761, 1390, 1309, 1228, 1065, 1016, 771 cm ⁻¹ .

[Reference Example 102]
5-hydroxy-4-phenylfuro [3 ′, 4 ′: 6,7] [1] benzofuro [2,3-b] pyridin-1 (3H) -one (I-102)
5-methoxy-4-phenylfuro [3 ′, 4 ′: 6,7] [1] benzofuro [2,3-b] pyridin-1 (3H) -one (I-101) (375 mg, 1.13 mmol), Sodium acetate (279 mg, 3.40 mmol) was dissolved in N, N-dimethylacetamide (7.5 ml) and stirred at 130 ° C. for 21 hours. The reaction mixture was poured into a 1N aqueous hydrochloric acid solution under ice cooling and stirred for 5 minutes. The resulting solid was collected by filtration while washing with water. The collected yellow solid was dried under reduced pressure at 50 ° C. for 15 hours to obtain 335 mg (81%) of the title compound.
MS (ESI) m / z: 318 (M + 1) ^<+> .
HRMS (EI) m / z: 317.0685 (Calcd for C 19 H 11 NO 4 317.0688).
¹ H-NMR (CDCl ₃ ) δ: 5.21 (2H, s), 7.36-7.47 (5H, m), 7.49 (1H, dd, J = 4.9, 7.6 Hz) , 8.42 (1H, dd, J = 1.7, 4.9 Hz), 8.51 (1H, dd, J = 1.7, 7.6H), 10.88 (1H, br s).
IR (ATR): 3518, 1761, 1610, 1394, 1315, 1209, 1063 cm ⁻¹ .

[Reference Example 103]
1-oxo-4-phenyl-1,3-dihydrofuro [3 ′, 4 ′: 6,7] [1] benzofuro [2,3-b] pyridin-5-yltrifluoromethanesulfonate (I-103)
5-hydroxy-4-phenylfuro [3 ′, 4 ′: 6,7] [1] benzofuro [2,3-b] pyridin-1 (3H) -one (I-102) (330 mg, 1.04 mmol). Dissolved in pyridine (6.6 ml). 4- (Dimethylamino) pyridine (26 mg, 0.21 mmol) and trifluoromethanesulfonic anhydride (527 μl, 3.12 mmol) were added at room temperature, and the mixture was stirred at room temperature for 6.5 hours under a nitrogen stream. The solution was fractionated with ethyl acetate and 1 molar aqueous hydrochloric acid. The aqueous layer was separated and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 3: 1, v / v) to give the title compound. 407 mg (87%) was obtained as a white solid.
HRMS (EI) m / z: 449.0187 (Calcd for C 20 H 10 F 3 NO 6 S 449.0181).
¹ H-NMR (CDCl ₃ ) δ: 5.33 (2H, s), 7.42-7.46 (2H, m), 7.52-7.59 (4H, m), 8.65 (1H , T, J = 1.7 Hz), 8.66 (1H, t, J = 1.7 Hz).
IR (KBr): 1780, 1599, 1415, 1402, 1223, 1132, 1063, 1036, 984, 885, 858, 822, 793, 768 cm ⁻¹ .

[Reference Example 104]
tert-Butyl [3- (1-oxo-4-phenyl-1,3-dihydrofuro [3 ′, 4 ′: 6,7] [1] benzofuro [2,3-b] pyridin-5-yl) cyclopent- 2-En-1-yl] carbamate (I-104)
1-oxo-4-phenyl-1,3-dihydrofuro [3 ′, 4 ′: 6,7] [1] benzofuro [2,3-b] pyridin-5-yl trifluoromethanesulfonate (I-103) (400 mg, 0.89 mmol) and tert-butyl (3-tri-n-butylstannylcyclopent-2-en-1-yl) carbamate (631 mg, 1.34 mmol) dissolved in 1,4-dioxane (8 ml) Lithium chloride (113 mg, 2.67 mmol), 2,6-ditert-butyl-p-cresol (4 mg, 0.02 mmol) and dichlorobis (triphenylphosphine) palladium (II) (94 mg, 0.13 mmol) at room temperature. ) Was added. The mixture was stirred at 110 ° C. for 21 hours under a nitrogen stream, and then cooled to room temperature. The insoluble material was filtered off while washing with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue obtained by distilling off the solvent was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 3: 2, v / v), and 274 mg (64%) of the title compound was white. Obtained as a wax.
MS (ESI) m / z: 483 (M + 1) ^<+> .
HRMS (FAB) m / z: 483.1891 (Calcd for C 29 H 27 N 2 O 5 483.1920).
¹ H-NMR (CDCl ₃ ) δ: 1.48 (9H, s), 1.60-1.70 (1H, m), 1.77 (1H, br s), 2.25-2.60 ( 1H, br), 4.70-4.95 (1H, br), 5.14 (1H, d, J = 15.9 Hz), 5.20 (1H, d, J = 15.9 Hz), 5. 92 (1H, br s), 7.20-7.30 (1H, m), 7.32-7.39 (2H, m), 7.41-7.56 (3H, m), 8.11 (1H, d, J = 7.6 Hz), 8.45 (1H, d, J = 3.7 Hz).
IR (ATR): 1770, 1705, 1496, 1456, 1392, 1228, 1165, 1030, 754 cm ⁻¹ .

[Example 26]
5- [3- (Dimethylamino) cyclopent-1-en-1-yl] -4-phenylfuro [3 ′, 4 ′: 6,7] [1] benzofuro [2,3-b] pyridine-1 (3H ) -On (# 26)

  tert-Butyl [3- (1-oxo-4-phenyl-1,3-dihydrofuro [3 ′, 4 ′: 6,7] [1] benzofuro [2,3-b] pyridin-5-yl) cyclopent- 2-En-1-yl] carbamate (I-104) (270 mg, 0.56 mmol) was dissolved in 4N hydrochloric acid 1,4-dioxane solution (5.4 ml) and stirred at room temperature for 1.5 hours. Tetrahydrofuran was added to the residue obtained by distilling off the solvent under reduced pressure, followed by azeotropic distillation. This operation was repeated twice more. The residue was dried under reduced pressure and then dissolved in methanol (6 ml) and chloroform (2 ml). Triethylamine (86 μl, 0.62 mmol) was added thereto, and the mixture was stirred at room temperature for 10 minutes. To this, acetic acid (200 μl, 3.36 mmol), 37% formaldehyde solution (273 μl, 3.36 mmol) and sodium cyanoborohydride (127 mg, 2.02 mmol) were sequentially added at room temperature, and the same temperature was maintained for 12.5 hours. Stir. Chloroform and saturated aqueous sodium hydrogen carbonate solution were added to the reaction solution, and the mixture was vigorously stirred at room temperature for 15 minutes. The aqueous layer was separated and extracted with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent was evaporated. The residue obtained was purified using preparative TLC (eluent; chloroform: methanol = 9: 1, v / v) to give 118 mg (51%) of the title compound. Was obtained as a white solid.

MS (ESI) m / z: 411 (M + 1) ⁺ .
HRMS (EI) m / z: 410.1628 (Calcd for C 26 H 22 N 2 O 3 410.1630).
¹ H-NMR (CDCl ₃ ) δ: 1.79-1.88 (1H, m), 2.00-2.55 (9H, m), 3.70-4.20 (1H, br), 5 .12 (1H, d, J = 6.1 Hz), 5.20 (H, d, J = 6.1 Hz), 5.93 (1H, q, J = 2.0 Hz), 7.29-7. 32 (2H, m), 7.34 (1H, dd, J = 4.9, 7.8 Hz), 7.40-7.49 (3H, m), 8.10-8.25 (1H, br ), 8.51 (1H, dd, J = 1.7, 4.9 Hz).
IR (ATR): 1770, 1456, 1392, 1338, 1059, 1030, 1007, 773 cm ⁻¹ .
Anal. _{Calcd for C 26 H 22 N 2} O 3 · 0.5H 2 O: C, 74.45; H, 5.53; N, 6.68. Found: C, 74.37; H, 5.38; N, 6.54.

[Reference Example 105]
5-acetyl-3-amino-4-fluoro-2-methoxy-6-methylbenzonitrile (I-105)
Under a nitrogen atmosphere, 900 mg (2.53 mmol) of N- (3-bromo-5-cyano-2-fluoro-6-methoxy-4-methylphenyl) -2,2,2-trifluoroacetamide (I-79) , Dichlorobis (triphenylphosphine) palladium in a toluene (25 ml) solution of tributyl (1-ethoxyvinyl) tin (1.10 g, 3.04 mmol) and 2,6-ditert-butyl-p-cresol (10 tablets) (II) (89 mg, 127 μmol) was added, and the mixture was heated to reflux for 18.5 hours. After cooling, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and a yellow oil was obtained from the eluate of n-hexane-ethyl acetate (5: 1, v / v). To a solution of this yellow oil in methanol (9 ml) was added concentrated hydrochloric acid (9 ml) at 0 ° C., and the mixture was stirred at room temperature for 88 hours. A 1N aqueous sodium hydroxide solution was added to the reaction mixture at 0 ° C., and the mixture was extracted with chloroform. Next, the combined organic layers were dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 463 mg (82%) of the title compound was obtained as a white solid from a fraction eluted with n-hexane-ethyl acetate (2: 1, v / v).
MS (ESI) m / z: 223 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 2.38 (3H, s), 2.53 (3H, d, J = 2.9 Hz), 3.94 (2H, brs), 4.04 (3H, s) ).
IR (ATR): 3448, 3350, 2227, 1687, 1631, 1570, 1481, 1340, 1200 cm ⁻¹ .

[Reference Example 106]
5-acetyl-3-bromo-4-fluoro-2-methoxy-6-methylbenzonitrile (I-106)
Under a nitrogen atmosphere, tert-butyl nitrite (379 µl, 3.19 mmol) was added to a suspension of copper bromide (781 mg, 3.50 mmol) in acetonitrile (10 ml), and then 5-acetyl-3- A suspension of amino-4-fluoro-2-methoxy-6-methylbenzonitrile (I-105) (354 mg, 1.59 mmol) in acetonitrile (6 ml) was added dropwise and stirred at the same temperature for 18 hours. After cooling, the reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 369 mg (81%) of the title compound was obtained as a white solid from a fraction eluted with n-hexane-ethyl acetate (5: 1, v / v).
¹ H-NMR (CDCl ₃ ) δ: 2.48 (3H, s), 2.56 (3H, d, J = 2.9 Hz), 4.11 (3H, s).
IR (ATR): 2229, 1701, 1581, 1358, 1327, 1252, 1155, 1088 cm ⁻¹ .

[Reference Example 107]
3-Bromo-4-fluoro-2-methoxy-6-methyl-5- (2-methyl-1,3-thiazol-4-yl) benzonitrile (I-107)
To a solution of 254 mg (888 μmol) of 5-acetyl-3-bromo-4-fluoro-2-methoxy-6-methylbenzonitrile (I-106) in acetic acid (7 ml), a solution of 156 mg (977 μmol) of bromine in acetic acid (2 ml) was added. After adding at room temperature, it stirred at 60 degreeC for 13 hours. After cooling, the solvent was distilled off under reduced pressure.
A solution of the obtained residue and 100 mg (1.33 mmol) of thioacetamide in ethanol (9 ml) was heated to reflux for 3.5 hours. After cooling, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture solution was extracted with ethyl acetate. Next, the combined organic layers were dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 155 mg (51%) of the title compound was obtained as an opalescent solid from the eluate of n-hexane-ethyl acetate (5: 1, v / v).
MS (ESI) m / z: 341, 343 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 2.43 (3H, s), 2.78 (3H, s), 4.09 (3H, s), 7.19 (1H, d, J = 1.0 Hz) ).
IR (ATR): 2231, 1458, 1435, 1400, 1333, 1292, 1169, 1084 cm ⁻¹ .

[Reference Example 108]
4-Fluoro-3- (2-fluoropyridin-3-yl) -2-methoxy-6-methyl-5- (2-methyl-1,3-thiazol-4-yl) benzonitrile (I-108)
Under a nitrogen atmosphere, 3-bromo-4-fluoro-2-methoxy-6-methyl-5- (2-methyl-1,3-thiazol-4-yl) benzonitrile (I107) (205 mg, 601 μmol), 2- Fluoro-3- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) pyridine (201 mg, 901 μmol), cesium carbonate (392 mg, 1.20 mmol) and tetrakis (triphenylphosphine) ) A suspension of palladium (0) (69 mg, 60 μmol) in toluene (3 ml) was heated to reflux for 17 hours. After cooling, the reaction solution was diluted with ethyl acetate, filtered, and the filtrate was washed with water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 105 mg (49%) of the title compound was obtained as a colorless oil from a fraction eluted with n-hexane-ethyl acetate (2: 1, v / v).
MS (ESI) m / z: 358 (M + 1) ^<+> .

[Example 27]
5-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -7-methyl-6- (2-methyl-1,3-thiazol-4-yl) [1] benzofuro [2,3- b] Pyridine-8-carbonitrile (# 27)

  Under a nitrogen atmosphere, 4-fluoro-3- (2-fluoropyridin-3-yl) -2-methoxy-6-methyl-5- (2-methyl-1,3-thiazol-4-yl) benzonitrile (I -108) A solution of 105 mg (294 μmol) and triethylamine 123 μl (881 μmol) in dimethyl sulfoxide (3 ml) was stirred at 130 ° C. for 18 hours, and (3S) -3- (dimethylamino) pyrrolidine (75 μl, 588 μmol) was stirred at the same temperature. The mixture was further stirred for 3 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform. Next, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, and then the aqueous layer was extracted with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give the crude title compound from the eluate of dichloromethane-methanol (20: 1, v / v), and 20 mg (16% of the title compound) was suspended and washed with diisopropyl ether. ) Was obtained as a light brown solid.

mp: 164-167 ° C.
MS (ESI) m / z: 418 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 1.75-1.90 (1H, m), 2.12-2.30 (1H, m), 2.24 (6H, s), 2.39 (3H , S), 2.60-2.90 (2H, m), 2.82 (3H, s), 3.07-3.25 (3H, m), 7.05 (1H, s), 7. 39-7.45 (1H, m), 8.11 (1H, d, J = 7.8 Hz), 8.46-8.49 (1H, m).
IR (ATR): 2220, 1591, 1456, 1390, 1373, 1209, 1169, 1146 cm ⁻¹ .
Anal. _{Calcd for C 23 H 23 N 5} OS · 0.5H 2 O: C, 64.77; H, 5.67; N, 16.42; S, 7.52. Found: C, 64.79; H, 5.47; N, 16.26; S, 7.64.

[Reference Example 109]
5-Fluoro-7-methyl-6- (2-methyl-1,3-thiazol-4-yl) [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-109)
Under a nitrogen atmosphere, 4-fluoro-3- (2-fluoropyridin-3-yl) -2-methoxy-6-methyl-5- (2-methyl-1,3-thiazol-4-yl) benzonitrile (I -108) (1.33 g, 3.72 mmol) and triethylamine (1.56 ml, 11.2 mmol) in dimethyl sulfoxide (37 ml) were stirred at 130 ° C. for 4.5 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform. Next, the organic layer was washed with water, and then the aqueous layer was extracted with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 282 mg (23%) of the title compound was obtained as a yellow solid from a fraction eluted with n-hexane-ethyl acetate (2: 1, v / v).
MS (ESI) m / z: 324 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.64 (3H, s), 2.82 (3H, s), 7.28 (1H, d, J = 0.7 Hz), 7.45 (1H, dd , J = 7.6, 4.9 Hz), 8.34 (1H, dd, J = 7.6, 1.7 Hz), 8.55 (1H, dd, J = 4.9, 1.7 Hz).
IR (ATR): 2229, 1591, 1390, 1309, 1227, 1184, 1130, 1111, 1070 cm ⁻¹ .

[Reference Example 110]
5-Methoxy-7-methyl-6- (2-methyl-1,3-thiazol-4-yl) [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-110)
Under a nitrogen atmosphere, 5-fluoro-7-methyl-6- (2-methyl-1,3-thiazol-4-yl) [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-109 ) To a mixed solution of 386 mg (1.19 mmol) in methanol-N, N-dimethylformamide (8 ml-4 ml), potassium carbonate (330 mg, 2.39 mmol) was added at room temperature and stirred at 70 ° C. for 2.5 hours. . After cooling, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform. Next, the organic layer was washed with water, and then the aqueous layer was extracted with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 318 mg (80%) of the title compound was obtained as a white solid from a fraction eluted with n-hexane-ethyl acetate (1: 1, v / v).
MS (ESI) m / z: 336 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.51 (3H, s), 2.83 (3H, s), 3.70 (3H, s), 7.20 (1H, s), 7.41 ( 1H, dd, J = 7.6, 4.9 Hz), 8.34 (1H, dd, J = 7.6, 1.5 Hz), 8.50 (1H, dd, J = 4.9, 1. 5 Hz).
IR (ATR): 2229, 1581, 1483, 1389, 1308, 1227, 1176 cm ⁻¹ .

[Reference Example 111]
8-cyano-7-methyl-6- (2-methyl-1,3-thiazol-4-yl) [1] benzofuro [2,3-b] pyridin-5-yltrifluoromethanesulfonate (I-111)
Under a nitrogen atmosphere, 5-methoxy-7-methyl-6- (2-methyl-1,3-thiazol-4-yl) [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-110 ) (312 mg, 930 μmol) in N, N-dimethylacetamide (9 ml) was added sodium acetate (229 mg, 2.79 mmol) at room temperature, 21 hours at 110 ° C., 5 hours at 120 ° C., 130 ° C. For 15 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in a chloroform-methanol mixed solvent. Next, the organic layer was washed with a 1N hydrochloric acid aqueous solution, and then the aqueous layer was extracted with a chloroform-methanol mixed solvent. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a light brown solid. Insoluble matter floating in the aqueous layer was collected by filtration to obtain a light brown solid, which was used for the next reaction. Under a nitrogen atmosphere, 4- (dimethylamino) pyridine (41 mg, 186 μmol) and trifluoromethanesulfonic anhydride (471 μl, 2.79 mmol) were added to the above-mentioned light brown solid pyridine (9 ml) solution at room temperature at the same temperature. For 27 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was dissolved in ethyl acetate, and the organic layer was washed with 1N aqueous hydrochloric acid. The aqueous layer was then extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 431 mg of the title compound containing impurities was obtained as a pale yellow solid from the fraction eluted with ethyl acetate.

[Reference Example 112]
tert-butyl [3- (8-cyano-7-methyl-6- (2-methyl-1,3-thiazol-4-yl) [1] benzofuro [2,3-b] pyridin-5-yl) cyclopent -2-en-1-yl] carbamate (I-112)
8-cyano-7-methyl-6- (2-methyl-1,3-thiazol-4-yl) [1] benzofuro [2,3-b] pyridin-5-yl trifluoromethane containing impurities under nitrogen atmosphere Sulfonate (I-111) (431 mg), tert-butyl (3-tri-n-butylstannylcyclopent-2-en-1-yl) carbamate (659 mg, 1.40 mmol), lithium chloride (118 mg, 2.79 mmol) ) And 2,6-ditert-butyl-p-cresol (5 tablets) in 1,4-dioxane (9 ml) were added dichlorobis (triphenylphosphine) palladium (II) (98 mg, 140 μmol). Heated to reflux for hours. After cooling, the solvent was distilled off under reduced pressure, n-hexane was added to the resulting residue, and the mixture was stirred at room temperature for 1 hour. Next, the precipitated solid was collected by filtration and then subjected to silica gel column chromatography to obtain 140 mg of the title compound containing impurities as a brown solid from the eluate of n-hexane-ethyl acetate (1: 1, v / v).
MS (ESI) m / z: 487 (M + 1) ^<+> .

[Example 28]
5- [3- (Dimethylamino) cyclopent-1-en-1-yl) -7-methyl-6- (2-methyl-1,3-thiazol-4-yl) [1] benzofuro [2,3- b] Pyridine-8-carbonitrile (# 28)
Tert-Butyl [3- (8-cyano-7-methyl-6- (2-methyl-1,3-thiazol-4-yl) [1] benzofuro [2,3-b] pyridine-5- To a solution of (yl) cyclopent-2-en-1-yl] carbamate (I-112) (132 mg) in tetrahydrofuran (3 ml) was added 5N aqueous hydrochloric acid solution under ice cooling, and the mixture was stirred at room temperature for 16 hours. Under ice-cooling, 1N aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with chloroform. Next, the combined organic layers were dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was suspended and washed with diisopropyl ether to obtain 63 mg of a yellow solid. Under a nitrogen atmosphere, a 37% formaldehyde solution (38 μl, 474 μmol) and sodium triacetoxyborohydride (84 mg, 395 μmol) were added to a 1,2-dichloroethane (2 ml) solution of the above yellow solid at room temperature, followed by acetic acid. (158 μl) was added under ice cooling, followed by stirring at room temperature for 80 minutes. Under ice-cooling, 1N aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with chloroform. Next, the combined organic layers were dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 21 mg of the title compound was obtained as a light brown solid from a chloroform-methanol (5: 1, v / v) eluate.

mp: 172-174 ° C.
MS (ESI) m / z: 415 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 1.81-1.95 (1H, m), 2.04-2.15 (1H, m), 2.19 (6H, s), 2.31-2 .47 (2H, m), 2.49 (3H, s), 2.77 (3H, s), 3.85-4.00 (1H, m), 5.85-5.88 (1H, m ), 7.03 (1H, s), 7.33-7.37 (1H, m), 8.08-8.14 (1H, m), 8.50 (1H, dd, J = 4.9) , 1.5 Hz).
Anal. _{Calcd for C 24 H 22 N 4} OS · 0.25H 2 O: C, 68.79; H, 5.41; N, 13.37. Found: C, 68.70; H, 5.36; N, 12.97.

[Reference Example 113]
2- (3-Bromo-5-cyano-2-fluoro-4-methoxy-6-methylphenyl) -2-oxoethyl acetate (I-113)
3-acetyl-5-bromo-4-fluoro-6-methoxy-2-methylbenzonitrile (I-106) (2.064 g, 7.21 mmol) was dissolved in acetic acid (30 ml) and bromine (1.268 g, 7.94 mmol) dissolved in acetic acid (10 ml) was added dropwise at room temperature. The mixture was stirred at 60 ° C. for 12 hours under a nitrogen stream, and then cooled to room temperature. The solvent was distilled off under reduced pressure, and the residue was fractionated with ethyl acetate and saturated brine. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, the solvent was distilled off under reduced pressure, and the residue was dissolved in acetic acid (30 ml). To this solution was added sodium acetate (5.92 g, 72.1 mmol) at room temperature, and the mixture was stirred at 95 ° C. for 17 hours under a nitrogen stream. After cooling to room temperature, the reaction mixture was fractionated with ethyl acetate and saturated brine. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 5: 1, v / v) to give the title compound 913 mg (37%) were obtained as a white solid.
MS (ESI) m / z: 344, 346 (M + 1) ^<+> .
^{_{HRMS (EI) m / z:}} 342.9843 (Calcd for C 13 H 11 79 BrFNO 4 342.9855), 344.9825 (Calcd for C 13 H 11 81 BrFNO 4 344.9835).
¹ H-NMR (CDCl ₃ ) δ: 2.17 (3H, s), 2.52 (3H, s), 4.14 (3H, s), 4.93 (2H, d, J = 2.4 Hz) ).
IR (ATR): 2231, 1757, 1716, 1213, 1128, 1086, 926, 795 cm ⁻¹ .

[Reference Example 114]
3-Bromo-4-fluoro-2-methoxy-6-methyl-5- (2-methyl-1,3-oxazol-4-yl) benzonitrile (I-114)
2- (3-Bromo-5-cyano-2-fluoro-4-methoxy-6-methylphenyl) -2-oxoethyl acetate (I-113) (1.195 g, 3.47 mmol) was dissolved in acetic acid (24 ml). Then, ammonium acetate (1.34 g, 17.36 mmol) was added at room temperature. The mixture was stirred at 120 ° C. for 12.5 hours under a nitrogen stream, and then cooled to room temperature. The solvent was distilled off under reduced pressure, and the residue was fractionated with ethyl acetate and saturated brine. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 3: 1, v / v) to give the title compound. 634 mg (56%) were obtained as an orange solid.
MS (ESI) m / z: 325, 327 (M + 1) ⁺ .
HRMS (EI) m / z: 323.9924 (Calcd for C ₁₃ H ₁₀ ⁷⁹ BrFN ₂ O ₂ 323.909), 325.9890 (Calcd for C ₁₃ H ₁₀ ⁸¹ BrFN ₂ O ₂ 344.835).
¹ H-NMR (CDCl ₃ ) δ: 2.56 (3H, s), 2.58 (3H, s), 4.12 (3H, s), 7.18 (1H, d, J = 2.0 Hz) ).
IR (ATR): 2225, 1539, 1456, 1406, 1333, 1144, 1086, 960, 921, 849, 727 cm ⁻¹ .

[Reference Example 115]
4-Fluoro-3- (2-fluoropyridin-3-yl) -2-methoxy-6-methyl-5- (2-methyl-1,3-oxazol-4-yl) benzonitrile (I-115)
3-bromo-4-fluoro-2-methoxy-6-methyl-5- (2-methyl-1,3-oxazol-4-yl) benzonitrile (I-114) (633 mg, 1.95 mmol), 2- Fluoro-3- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) pyridine (869 mg, 3.89 mmol) and cesium carbonate (1.27 g, 3.89 mmol) were added to toluene. (15 ml) and tetrakis (triphenylphosphine) palladium (0) (225 mg, 0.19 mmol) was added at room temperature. The mixture was stirred at 115 ° C. for 18 hours under a nitrogen stream and then cooled to room temperature. The insoluble material was filtered off while washing with ethyl acetate. The filtrate was washed with saturated brine and then dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 2: 1, v / v) to give the title compound. 431 mg (65%) was obtained as a white solid.
MS (ESI) m / z: 342 (M + 1) ^<+> .
HRMS (EI) m / z: 341.0965 (Calcd for C 18 H 13 F 2 N 3 O 2 341.0976).
¹ H-NMR (CDCl ₃ ) δ: 2.55 (3H, s), 2.66 (3H, s), 3.85 (3H, s), 7.17 (1H, d, J = 2.0 Hz) ).
IR (ATR): 2224, 1568, 1439, 1402, 1331, 1201, 1132, 1084, 920, 798, 762 cm ⁻¹ .

[Reference Example 116]
5-Fluoro-7-methyl-6- (2-methyl-1,3-oxazol-4-yl) [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-116)
4-fluoro-3- (2-fluoropyridin-3-yl) -2-methoxy-6-methyl-5- (2-methyl-1,3-oxazol-4-yl) benzonitrile (I-115) ( 428 mg, 1.25 mmol) was dissolved in dimethyl sulfoxide (8.5 ml), and triethylamine (524 μl, 3.76 mmol) was added at room temperature. The reaction solution was stirred at 120 ° C. for 1.5 hours under a nitrogen stream. After cooling to room temperature, the reaction mixture was fractionated with ethyl acetate and saturated brine. The aqueous layer was extracted twice more with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 1: 1, v / v) to give the title compound. 186 mg (48%) was obtained as a white solid.
MS (ESI) m / z: 308 (M + 1) ⁺ .
HRMS (EI) m / z: 307.0767 (Calcd for C 17 H 10 FN 3 O 2 307.0757).
¹ H-NMR (CDCl ₃ ) δ: 2.60 (3H, s), 2.76 (3H, s), 7.24 (1H, d, J = 1.7 Hz), 7.49 (1H, dd , J = 4.9, 7.6 Hz), 8.38 (1H, dd, J = 1.7, 7.6 Hz), 8.58 (1H, dd, J = 1.7, 4.9 Hz).
IR (ATR): 2231, 1591, 1564, 1392, 1311, 1217, 1138, 1113, 825, 802, 773, 756, 731 cm ⁻¹ .

[Example 29]
5-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -7-methyl-6- (2-methyl-1,3-oxazol-4-yl) [1] benzofuro [2,3- b] Pyridine-8-carbonitrile (# 29)
5-Fluoro-7-methyl-6- (2-methyl-1,3-oxazol-4-yl) [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-116) (185 mg, 0.60 mmol) was dissolved in dimethyl sulfoxide (4 ml), and triethylamine (126 μl, 0.90 mmol) and (3S) -3- (dimethylamino) pyrrolidine (99 μl, 0.78 mmol) were added at room temperature. The reaction was stirred at 90 ° C. for 12.5 hours under a nitrogen stream and then cooled to room temperature. The reaction mixture was fractionated with ethyl acetate and saturated brine. The aqueous layer was extracted twice more with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using preparative TLC (eluent; chloroform: methanol = 9: 1, v / v) to give 216 mg (89%) of the title compound. Was obtained as a brown solid.

MS (ESI) m / z: 402 (M + 1) ^<+> .
HRMS (EI) m / z: 401.1845 (Calcd for C 23 H 23 N 5 O 2 401.1852).
¹ H-NMR (CDCl ₃ ) δ: 1.88 (1H, dq, J = 8.3, 12.2 Hz), 2.14-2.25 (1H, m), 2.24 (6H, s) , 2.46 (3H, s), 2.58 (3H, s), 2.78 (1H, dq, J = 7.6, 7.8 Hz), 3.04 (1H, dd, J = 7. 6, 9.5 Hz), 3.11-3.20 (2 H, m), 3.23 (1 H, dd, J = 7.1, 9.5 Hz), 6.97 (1 H, s), 7. 43 (1H, dd, J = 4.9, 7.6 Hz), 8.14 (1H, dd, J = 1.7, 7.6 Hz), 8.47 (1H, dd, J = 1.7, 4.9 Hz).
IR (ATR): 2224, 1614, 1587, 1570, 1456, 1383, 1363, 1207, 1174, 1120, 810 cm ⁻¹ .
Anal. _{Calcd for C 23 H 23 N 5} O 2 · 0.25H 2 O: C, 68.05; H, 5.83; N, 17.25. Found: C, 68.27; H, 5.71; N, 16.95.

[Reference Example 117]
5-Acetyl-4-fluoro-3- (2-fluoropyridin-3-yl) -2-methoxy-6-methylbenzonitrile (I-117)
Under a nitrogen atmosphere, 5-acetyl-3-bromo-4-fluoro-2-methoxy-6-methylbenzonitrile (I-106) (1.00 g, 3.50 mmol), 2-fluoro-3- (4,4 , 5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) pyridine (1.17 g, 5.24 mmol), cesium carbonate (2.28 g, 7.00 mmol) and tetrakis (triphenylphosphine) palladium. A suspension of (0) (404 mg, 350 μmol) in toluene (18 ml) was heated to reflux for 19 hours. After cooling, the reaction solution was diluted with ethyl acetate, filtered, and the filtrate was washed with water and saturated brine. Next, the organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and 806 mg (76%) of the title compound was obtained as a pale yellow solid from a fraction eluted with n-hexane-ethyl acetate (3: 1, v / v).
MS (ESI) m / z: 303 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.56-2.58 (6H, m), 3.85 (3H, s), 7.32-7.36 (1H, m), 7.76-7 .81 (1H, m), 8.33-8.36 (1H, m).
IR (ATR): 2225, 1701, 1560, 1442, 1433, 1419, 1323, 1194, 1090 cm ⁻¹ .

[Example 30]
6-acetyl-5-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -7-methyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (# 30)
Under a nitrogen atmosphere, 465 mg (1.54 mmol) and (3S)-of 5-acetyl-4-fluoro-3- (2-fluoropyridin-3-yl) -2-methoxy-6-methylbenzonitrile (I-117) A solution of 3- (dimethylamino) pyrrolidine (429 μl, 3.38 mmol) in dimethyl sulfoxide (15 ml) was stirred at 100 ° C. for 14.5 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform. Next, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, and then the aqueous layer was extracted with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give the title compound from a fraction eluted with dichloromethane-methanol (9: 1, v / v). 4%) was obtained as a light brown solid. A total of 380 mg (68%) of the title compound was obtained.

mp: 174-177 ° C.
MS (ESI) m / z: 363 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.02-2.15 (1H, m), 2.28-2.38 (1H, m), 2.31 (6H, s), 2.53-2 .54 (3H, m), 2.55-2.56 (3H, m), 2.89-2.98 (1H, m), 3.33-3.39 (1H, m), 3.46 -3.52 (3H, m), 7.42-7.47 (1H, m), 8.18 (1H, d, J = 7.6 Hz), 8.49-8.52 (1H, m) .
IR (ATR): 2227, 1703, 1458, 1389, 1346, 1211, 1151 cm ⁻¹ .
Anal. Calcd for C ₂₁ H ₂₂ N ₄ O ₂ .0.25H ₂ O: C, 68.74; H, 6.18; N, 15.27. Found: C, 69.03; H, 6.09; N, 15.07.

[Example 31]
5-[(3S) -3- (Dimethylamino) pyrrolidin-1-yl] -7-methyl-6- (1H-pyrazol-3-yl) [1] benzofuro [2,3-b] pyridine-8- Carbonitrile (# 31)
Under a nitrogen atmosphere, 6-acetyl-5-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -7-methyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (# 30) A suspension of N, N-dimethylformamide dimethyl acetal (3 ml) in (100 mg, 276 μmol) was heated to reflux for 5 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to the next reaction. Under a nitrogen atmosphere, hydrazine monohydrate (20 μl, 414 μmol) was added to an ethanol (3 ml) suspension of the above residue at room temperature, and the mixture was heated to reflux for 46 hours. After cooling, the reaction solution was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give the crude title compound from the eluate of dichloromethane-methanol (5: 1, v / v), and suspended and washed with diisopropyl ether to give 48 mg (45% of the title compound). ) Was obtained as a light brown solid.

mp: 196-199 ° C.
MS (ESI) m / z: 387 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 1.77-1.88 (1H, m), 2.07-2.17 (1H, m), 2.22 (6H, s), 2.39 (3H , S), 2.69-2.77 (1H, m), 2.81-2.88 (1H, m), 2.99-3.07 (1H, m), 3.11-3.19. (1H, m), 3.23 (1H, dd, J = 9.3, 6.6 Hz), 6.34 (1H, d, J = 2.2 Hz), 7.41 (1H, dd, J = 7.6, 5.0 Hz), 7.74 (1H, d, J = 2.2 Hz), 8.09 (1H, dd, J = 7.6, 1.7 Hz), 8.45-8.47. (1H, m).
IR (ATR): 2222, 1589, 1466, 1392, 1219, 1205 cm ⁻¹ .
Anal. _{Calcd for C 22 H 22 N 6} O · 0.75H 2 O: C, 66.07; H, 5.92; N, 21.01. Found: C, 66.00; H, 5.79; N, 20.77.

[Example 32]
5-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -6- (isoxazol-5-yl) -7-methyl [1] benzofuro [2,3-b] pyridine-8-carbo Nitrile (# 32)

  Under a nitrogen atmosphere, 6-acetyl-5-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -7-methyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (# 30) A suspension of (153 mg, 422 μmol) in N, N-dimethylformamide dimethylacetal (4 ml) was heated to reflux for 4 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to the next reaction. Under a nitrogen atmosphere, hydroxylamine hydrochloride (80 mg, 1.27 mmol) was added to a mixed solution of the above residue in ethanol-water (4 ml-400 μl) at room temperature, and the mixture was heated to reflux for 1.5 hours. After cooling, the reaction solution was concentrated under reduced pressure. The obtained residue was azeotroped with toluene, dissolved in tetrahydrofuran (4 ml), concentrated hydrochloric acid (2 ml) was added at room temperature, and the mixture was stirred for 68 hours. 1N Aqueous sodium hydroxide solution was added to the reaction mixture under ice cooling, and the mixture was extracted with chloroform. Next, the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain the crude title compound from an eluate of dichloromethane-methanol (5: 1, v / v), and 79 mg (48%) of the title compound was suspended and washed with diisopropyl ether. ) Was obtained as a pale yellow solid.

mp: 158-160 ° C.
MS (ESI) m / z: 388 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 1.80-1.91 (1H, m), 2.11-2.21 (1H, m), 2.23 (6H, s), 2.43 (3H , S), 2.73-2.83 (1H, m), 2.97-3.04 (1H, m), 3.11-3.24 (3H, m), 6.39 (1H, d) , J = 1.7 Hz), 7.45 (1H, dd, J = 7.7, 4.9 Hz), 8.14 (1H, dd, J = 7.7, 1.7 Hz), 8.44 ( 1H, d, J = 1.7 Hz), 8.50 (1H, dd, J = 4.9, 1.7 Hz).
IR (ATR): 2225, 1606, 1587, 1464, 1390, 1155 cm ⁻¹ .
Anal. Calcd for C ₂₂ H ₂₁ N ₅ O ₂ .0.25H ₂ O: C, 67.42; H, 5.53; N, 17.87. Found: C, 67.61; H, 5.43; N, 17.65.

[Reference Example 118]
6-[(2E) -3- (Dimethylamino) but-2-enoyl] -5-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -7-methyl [1] benzofuro [2, 3-b] pyridine-8-carbonitrile (I-118)
6-acetyl-5-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -7-methyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (# 30) A suspension of (400 mg, 1.10 mmol) in N, N-dimethylacetamide dimethylacetal (6 ml) was stirred at 80-90 ° C. for 48.5 hours. After cooling, the residue obtained by concentrating the reaction solution under reduced pressure was subjected to silica gel column chromatography. Got as.
MS (ESI) m / z: 432 (M + 1) ⁺ .

[Example 33]
5-[(3S) -3-Dimethylaminopyrrolidin-1-yl] -7-methyl-6- (3-methylisoxazol-5-yl) [1] benzofuro [2,3-b] pyridine-8- Carbonitrile (# 33)
6-[(2E) -3- (dimethylamino) but-2-enoyl] -5-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -7-methyl [1] under nitrogen atmosphere Hydroxylamine hydrochloride (96 mg, 1.38 mmol) was added to a mixed solution of benzofuro [2,3-b] pyridine-8-carbonitrile (I-118) (198 mg, 459 μmol) in ethanol-water (5 ml-500 μl) at room temperature. In addition, the mixture was heated to reflux for 3.5 hours. After cooling, the reaction solution was concentrated under reduced pressure. The obtained residue was azeotroped with toluene, dissolved in tetrahydrofuran (4 ml), concentrated hydrochloric acid (2 ml) was added at room temperature, and the mixture was stirred for 24 hours. 1N Aqueous sodium hydroxide solution was added to the reaction mixture under ice cooling, and the mixture was extracted with chloroform. Next, the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to give the crude title compound from a fraction eluted with dichloromethane-methanol (5: 1, v / v), and suspended and washed with diisopropyl ether to give 58 mg (32%) of the title compound. ) Was obtained as a light brown solid.

mp: 159-162 ° C.
MS (ESI) m / z: 402 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 1.81-1.93 (1H, m), 2.12-2.28 (1H, m), 2.24 (6H, s), 2.43 (3H , S), 2.44 (3H, s), 2.74-2.83 (1H, m), 3.02-3.27 (4H, m), 6.21 (1H, s), 7. 42-7.47 (1H, m), 8.12-8.17 (1H, m), 8.48-8.51 (1H, m).
IR (ATR): 2224, 1603, 1583, 1468, 1396, 1205, 1149 cm ⁻¹ .
Anal. _{Calcd for C 23 H 23 N 5} O 2 · 0.25H 2 O: C, 68.05; H, 5.83; N, 17.25. Found: C, 68.36; H, 5.70; N, 17.27.

[Reference Example 119]
3-Amino-4-fluoro-2-methoxy-6-methyl-5-[(E) -2-phenylvinyl] benzonitrile (I-119)
3-amino-5-bromo-4-fluoro-2-methoxy-6-methylbenzonitrile (I-73) (10.0 g, 38.60 mmol), (E) -2-phenylvinylboronic acid (11.78 g) , 77.20 mmol) and tripotassium phosphate (16.39 g, 77.20 mmol) were suspended in 1,4-dioxane (200 ml) and tetrakis (triphenylphosphine) palladium (0) (4.46 g, 3.86 mmol) was added. The mixture was stirred at 105 ° C. for 17 hours under a nitrogen stream. After cooling to room temperature, saturated brine was added to the reaction solution. The resulting insoluble material was filtered off while washing with ethyl acetate. The organic layer of the filtrate was distilled off under reduced pressure, and the aqueous layer was extracted with ethyl acetate three times. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was subjected to column chromatography using silica gel. From the n-hexane-ethyl acetate (4: 1, v / v) flow fraction, the title compound 10. 04 g (92%) were obtained as a pale orange gel.
MS (ESI) m / z: 283 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.54 (3H, s), 3.65-4.10 (2H, br), 4.01 (3H, s), 6.91 (1H, d, J = 16.6 Hz), 7.05 (1H, d, J = 16.6 Hz), 7.29-7.32 (1H, m), 7.35-7.40 (2H, m), 7.48. -7.52 (2H, m).

[Reference Example 120]
3-Bromo-4-fluoro-2-methoxy-6-methyl-5-[(E) -2-phenylvinyl] benzonitrile (I-120)
Copper (II) bromide (7.94 g, 35.56 mmol) was dissolved in acetonitrile (100 ml), and tert-butyl nitrite (purity 90%; 5.64 ml, 42.68 mmol) was added at room temperature. The suspension was stirred for 10 minutes at 60 ° C., and then 3-amino-4-fluoro-2-methoxy-6-methyl-5-[(E) -2-phenylvinyl] benzonitrile (I-119) ( A solution prepared by dissolving 10.04 g, 35.56 mmol) in acetonitrile (100 ml) was added dropwise at the same temperature over 30 minutes. After stirring at the same temperature for 3 hours, the mixture was cooled to room temperature. To this reaction solution was added 1N aqueous hydrochloric acid solution at 0 ° C., and the mixture was stirred for 10 minutes. The residue obtained by evaporating the solvent under reduced pressure was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified by column chromatography using silica gel (eluent; n-hexane: ethyl acetate = 19: 1, v / v). 9.217 g (75%) of compound were obtained. Further, the fraction containing impurities was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 95: 5, v / v) to obtain 403 mg (3%) of the title compound as a white solid. (Total 9.62 g, 78%).
MS (ESI) m / z: 346, 348 (M + 1) ^<+> .
HRMS (EI) m / z: 345.0165 (Calcd for C ₁₇ H ₁₃ ⁷⁹ BrFNO 345.0165), 347.0137 (Calcd for C ₁₇ H ₁₃ ⁸¹ BrFNO 347.0144)
¹ H-NMR (CDCl ₃ ) δ: 2.58 (3H, s), 4.06 (3H, s), 6.88 (1H, d, J = 16.6 Hz), 7.06 (1H, d , J = 16.6 Hz).
IR (ATR): 2227, 1406, 1115, 962, 748 cm ⁻¹ .

[Reference Example 121]
4-Fluoro-3- (2-fluoropyridin-3-yl) -2-methoxy-6-methyl-5-[(E) -2-phenylvinyl] benzonitrile (I-121)
3-Bromo-4-fluoro-2-methoxy-6-methyl-5-[(E) -2-phenylvinyl] benzonitrile (I-120) (9.21 g, 26.60 mmol), 2-fluoro-3 -(4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) pyridine (11.86 g, 53.21 mmol) and cesium carbonate (17.34 g, 53.21 mmol) in toluene (184 ml) and tetrakis (triphenylphosphine) palladium (0) (3.08 g, 2.66 mmol) was added at room temperature. The mixture was stirred at 110 ° C. for 20 hours under a nitrogen stream. After cooling to room temperature, saturated brine was added to the reaction solution, and the mixture was vigorously stirred at the same temperature for 30 minutes. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified by column chromatography using silica gel (eluent; n-hexane: ethyl acetate = 5: 1, v / v). 7.039 g (73%) of compound was obtained as an orange gel.
MS (ESI) m / z: 363 (M + 1) ^<+> .
HRMS (EI) m / z: 362.1225 (Calcd for C 22 H 16 F 2 N 2 O 362.1230).
¹ H-NMR (CDCl ₃ ) δ: 2.68 (3H, s), 3.79 (3H, s), 6.92 (1H, d, J = 16.6 Hz), 7.08 (1H, d , J = 16.6 Hz), 7.27-7.40 (4H, m), 7.50 (1H, d, J = 7.3 Hz), 7.82 (1H, ddd, J = 2.0, 7.6, 11.2 Hz), 8.30-8.34 (1 H, m).
IR (ATR): 2227, 1593, 1560, 1439, 1404, 1115, 1099, 966 cm ⁻¹ .

[Reference Example 122]
4-Fluoro-3- (2-fluoropyridin-3-yl) -5-formyl-2-methoxy-6-methylbenzonitrile (I-122)
4-Fluoro-3- (2-fluoropyridin-3-yl) -2-methoxy-6-methyl-5-[(E) -2-phenylvinyl] benzonitrile (I-121) (1.0 g, 2 .76 mmol) was dissolved in tert-butanol (20 ml) and water (10 ml), and pyridine (670 μl, 8.28 mmol) was added at room temperature. After stirring this solution for 10 minutes, sodium metaperiodate (1.77 g, 8.28 mmol) and then osmium tetroxide (several grains) were added at the same temperature. After stirring at the same temperature for 7.5 hours, water (10 ml) and sodium sulfite (1.04 g, 8.28 mmol) were added to the reaction solution. After stirring at room temperature for 13 hours, the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 4: 1, v / v) to give the title compound. 431 mg (54%) was obtained as a white solid.
MS (ESI) m / z: 289 (M + 1) ⁺ .
HRMS (FAB) m / z: 289.0770 (Calcd for C 15 H 11 F 2 N 2 O 2 289.0789).
¹ H-NMR (CDCl ₃ ) δ: 2.91 (3H, s), 3.94 (3H, s), 7.38 (1H, ddd, J = 1.9, 4.9, 7.3 Hz) 7.82 (1H, ddd, J = 1.9, 7.3, 9.0 Hz), 8.37 (1H, ddd, J = 1.0, 1.9, 4.9 Hz), 10.43 (1H, s).
IR (ATR): 2231, 1697, 1593, 1560, 1439, 1394, 1323, 1113, 1099, 789 cm ⁻¹ .

[Reference Example 123]
4-Fluoro-3- (2-fluoropyridin-3-yl) -2-methoxy-6-methyl-5-vinylbenzonitrile (I-123)
Methyltriphenylphosphonium bromide (248 mg, 0.69 mmol) was dissolved in tetrahydrofuran (1.5 ml) and n-butyllithium (1.60 M n-hexane solution) (390 μl, 0.63 mmol) at 0 ° C. under a nitrogen stream. Was added. After stirring at the same temperature for 30 minutes, 4-fluoro-3- (2-fluoropyridin-3-yl) -5-formyl-2-methoxy-6-methylbenzonitrile (I-122) (100 mg, 0.35 mmol) ) In tetrahydrofuran (1.5 ml) was added dropwise. After stirring at the same temperature for 2 hours, a saturated aqueous ammonium chloride solution was added to the reaction solution. This was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 7: 1, v / v) to give the title compound 36 mg (36%) were obtained as a colorless oil.
MS (ESI) m / z: 287 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.61 (3H, s), 3.78 (3H, s), 5.69 (1H, dt, J = 1.5, 11.7 Hz), 5.71 (1H, dt, J = 1.5, 17.8 Hz), 6.59 (1H, dd, J = 11.7, 17.8 Hz), 7.33 (1H, ddd, J = 2.0, 4 .9, 7.6 Hz), 7.80 (1H, ddd, J = 2.0, 7.6, 8.8 Hz), 8.32 (1H, ddd, J = 1.0, 2.0, 4) .9 Hz).

[Reference Example 124]
3-[(1S) -1,2-dihydroxyethyl] -4-fluoro-5- (2-fluoropyridin-3-yl) -6-methoxy-2-methylbenzonitrile (I-124)
4-Fluoro-3- (2-fluoropyridin-3-yl) -2-methoxy-6-methyl-5-vinylbenzonitrile (I-123) (35 mg, 0.12 mmol) was added to tert-butanol (1 ml) and It melt | dissolved in water (1 ml), AD-mix- (alpha) (172 mg) and methanesulfonamide (12 mg, 0.12 mmol) were added at 0 degreeC, and it stirred at the same temperature for 24 hours. Sodium sulfite (180 mg) was added to the reaction solution at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours. The solution was fractionated with ethyl acetate and saturated brine. The aqueous layer was further extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using preparative TLC (chloroform: methanol = 94: 6, v / v) to give 39 mg (quant.) Of the title compound as a colorless gel. Got as.
MS (ESI) m / z: 321 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 2.70 (3H, s), 2.90-3.15 (1H, br), 3.35-3.70 (1H, br), 3.74 (3H , S), 3.65-3.80 (1H, m), 3.98 (1H, q, J = 9.8 Hz), 5.24 (1H, br s), 7.32 (1H, t, J = 4.9 Hz), 7.79 (1H, t, J = 7.6 Hz), 8.29 (1H, d, J = 4.9 Hz).

[Reference Example 125]
3-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] -4-fluoro-5- (2-fluoropyridin-3-yl) -6-methoxy-2-methylbenzonitrile (I-125)
3-[(1S) -1,2-dihydroxyethyl] -4-fluoro-5- (2-fluoropyridin-3-yl) -6-methoxy-2-methylbenzonitrile (I-124) (39 mg, 0 .12 mmol) was dissolved in N, N-dimethylformamide (2 ml) and 2,2-dimethoxypropane (45 μl, 0.37 mmol) and pyridinium p-toluenesulfonic acid (9 mg, 0.04 mmol) were added at room temperature. . After stirring for 18 hours at room temperature under a nitrogen stream, 2,2-dimethoxypropane (45 μl, 0.37 mmol) and pyridinium p-toluenesulfonic acid (9 mg, 0.04 mmol) were added again. After stirring at room temperature for 24 hours, the reaction mixture was fractionated with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The aqueous layer was extracted again with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using preparative TLC (n-hexane: ethyl acetate = 1: 1, v / v) to give 31 mg (70%) of the title compound. Was obtained as a colorless gel.
MS (ESI) m / z: 361 (M + 1) ⁺ .
HRMS (EI) m / z: 360.1283 (Calcd for C 19 H 18 F 2 N 2 O 3 360.1286).
¹ H-NMR (CDCl ₃ ) δ: 1.45 and 1.46 (each 1.5H, each), 1.55 and 1.57 (each 1.5H, each), 2.72 and 2. 73 (each 1.5H, each), 3.77 and 3.78 (each 1.5H, each), 4.00 (1H, q, J = 7.6 Hz), 4.28 (1H, q, J = 7.6 Hz), 5.51 (1H, dt, J = 7.6, 14.9 Hz), 7.32 (1H, ddd, J = 1.7, 4.9, 7.3 Hz), 7 .74-7.81 (1H, m), 8.32 (1H, d, J = 4.9 Hz).
IR (ATR): 2229, 1597, 1568, 1410, 1381, 1209, 1157, 1119, 1099, 1051, 858 cm ⁻¹ .

[Reference Example 126]
6-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] -5-fluoro-7-methyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I -126)
3-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] -4-fluoro-5- (2-fluoropyridin-3-yl) -6-methoxy-2-methylbenzonitrile (I-125) (30 mg, 0.08 mmol) was dissolved in dimethyl sulfoxide (1.5 ml), and triethylamine (35 μl, 0.25 mmol) was added at room temperature. The mixture was stirred at 110 ° C for 24 hours under a nitrogen stream. The reaction mixture was cooled to room temperature, and fractionated with ethyl acetate and saturated brine. The aqueous layer was further extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using preparative TLC (n-hexane: ethyl acetate = 1: 1, v / v) to give 21 mg (78%) of the title compound. Was obtained as a colorless gel.
MS (ESI) m / z: 327 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 1.51 (3H, s), 1.63 (3H, s), 2.85 (3H, s), 4.10 (1H, dd, J = 1.2 , 8.1 Hz), 4.35 (1H, t, J = 8.1 Hz), 5.63 (1H, t, J = 8.1 Hz), 7.46 (1H, dd, J = 4.9, 7.6 Hz), 8.36 (1H, dd, J = 1.7, 7.6 Hz), 8.54 (1H, dd, J = 1.7, 4.9 Hz).

[Example 34]
5-[(3S) -3- (Dimethylamino) pyrrolidin-1-yl] -6-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] -7-methyl [1] Benzofuro [2,3-b] pyridine-8-carbonitrile (# 34)
6-[(4S) -2,2-dimethyl-1,3-dioxolan-4-yl] -5-fluoro-7-methyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I -126) (21 mg, 0.06 mmol) was dissolved in dimethyl sulfoxide (1 ml) and triethylamine (14 μl, 0.10 mmol) and (3S) -3- (dimethylamino) pyrrolidine (12 μl, 0.1 mmol) at room temperature. Was added. After stirring at 100 ° C. for 28 hours, the mixture was cooled to room temperature. The reaction mixture was fractionated with ethyl acetate and saturated brine. The aqueous layer was further extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, the solvent was evaporated, and the resulting residue was purified using preparative TLC (chloroform: methanol = 95: 5, v / v) to give 11 mg (41%) of the title compound as a light brown color. Obtained as a solid.

MS (ESI) m / z: 421 (M + 1) ⁺ .
HRMS (FAB) m / z: 421.2236 (Calcd for C 24 H 29 N 4 O 3 421.2240).
¹ H-NMR (CDCl ₃ ) δ: 1.50 (3H, s), 1.66 (3H, s), 2.18-2.30 (1H, m), 2.37 (6H, s), 2.35-2.49 (1H, m), 2.85 (3H, s), 3.01-3.12 (1H, m), 3.37 (1H, t, J = 8.0 Hz), 3.45 (1H, dt, J = 7.1, 9.0 Hz), 3.58 (1H, t, J = 8.0 Hz), 4.00 (1H, t, J = 8.0 Hz), 4 .30 (1H, t, J = 8.0 Hz), 5.90 (1H, t, J = 8.0 Hz), 7.43 (1H, dd, J = 4.9, 7.6 Hz), 8. 24 (1H, d, J = 1.5, 7.6 Hz), 8.49 (1H, dd, J = 1.5, 4.9 Hz).
IR (ATR): 2227, 1512, 1466, 1394, 1377, 1207, 1047, 862, 754 cm ⁻¹ .

[Reference Example 127]
5-Fluoro-7-methyl-6-[(E) -2-phenylvinyl] [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-127)
4-Fluoro-3- (2-fluoropyridin-3-yl) -2-methoxy-6-methyl-5-[(E) -2-phenylvinyl] benzonitrile (I-121) (5.03 g, 13 .88 mmol) was dissolved in dimethyl sulfoxide (100 ml), and triethylamine (5.8 ml, 41.64 mmol) was added at room temperature. The mixture was stirred for 10 hours while gradually warming from room temperature to 100 ° C. After cooling to room temperature, the solvent was distilled off under reduced pressure. The residue was fractionated with ethyl acetate and saturated brine. The aqueous layer was further extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using medium pressure liquid chromatography (eluent; chloroform) to give 2.897 g (64%) of the title compound as a white solid. .
MS (ESI) m / z: 329 (M + 1) ^<+> .
HRMS (EI) m / z: 328.1008 (Calcd for C ₂₁ H ₁₃ FN ₂ O 328.1010).
¹ H-NMR (CDCl ₃ ) δ: 2.77 (3H, s), 6.98 (1H, d, J = 16.4 Hz), 7.15 (1H, d, J = 16.4 Hz), 7 .32-7.46 (4H, m), 7.53-7.57 (2H, m), 8.35 (1H, dd, J = 1.7, 7.6 Hz), 8.52 (1H, dd, J = 1.7, 4.9 Hz).
IR (ATR): 2227, 1591, 1408, 1225, 1116, 960, 808, 777, 742 cm ⁻¹ .

[Reference Example 128]
tert-butyl ((3S) -1- {8-cyano-7-methyl-6-[(E) -2-phenylvinyl] [1] benzofuro [2,3-b] pyridin-5-yl} pyrrolidine- 3-ylcarbamate (I-128)
5-Fluoro-7-methyl-6-[(E) -2-phenylvinyl] [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-127) (300 mg, 0.91 mmol). Dissolved in dimethyl sulfoxide (6 ml), triethylamine (191 μl, 1.37 mmol) and (3S) -3- (tert-butoxycarbonylamino) pyrrolidine (255 mg, 1.37 mmol) were added at room temperature. The reaction solution was stirred at 100 ° C. for 25 hours under a nitrogen stream. After cooling to room temperature, this was fractionated with ethyl acetate and saturated brine. The aqueous layer was further extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 1: 1, v / v) to give the title compound. 202 mg (45%) were obtained as a pale yellow solid.
MS (ESI) m / z: 495 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.89-1.99 (1H, m), 2.34-2.44 (1H, m), 2.63 (3H , S), 3.28 (1H, dd, J = 4.4, 9.8 Hz), 3.45 (1H, ddd, J = 6.1, 8.1, 9.8 Hz), 3.62 ( 1H, ddd, J = 6.1, 8.1, 9.8 Hz), 3.77 (1H, dd, J = 6.1, 9.8 Hz), 4.25-4.45 (1H, m) 4.85-5.00 (1H, m), 6.50 (1H, d, J = 16.6 Hz), 7.14 (1H, d, J = 16.6 Hz), 7.32-7. 38 (2H, m), 7.43 (2H, dd, J = 7.3, 7.8 Hz), 7.54 (2H, d, J = 7.3 Hz), 7.98 (1H, dd, J = 1.7, 7.8 Hz), 8. 5 (1H, dd, J = 1.7,4.9Hz).

[Reference Example 129]
tert-butyl {(3S) -1- [8-cyano-7-methyl-6- (2-phenylethyl) [1] benzofuro [2,3-b] pyridin-5-yl] pyrrolidin-3-yl} Carbamate (I-129)
tert-butyl ((3S) -1- {8-cyano-7-methyl-6-[(E) -2-phenylvinyl] [1] benzofuro [2,3-b] pyridin-5-yl} pyrrolidine- 3-ylcarbamate (I-128) (102 mg, 0.21 mmol) was dissolved in ethyl acetate (3 ml), and 10% palladium carbon (20 mg) was added at room temperature. The catalyst was filtered off while washing with ethyl acetate, and the filtrate was concentrated under reduced pressure, the residue was dissolved again in ethyl acetate (3 ml), and 10% palladium carbon (102 mg) was added at room temperature. The suspension was stirred at room temperature for 14 hours under a normal pressure hydrogen stream, the catalyst was filtered off while washing with ethyl acetate, and the filtrate was concentrated under reduced pressure. TLC (Rum: methanol = 97: 3, v / v) to obtain 76 mg (74%) of the title compound as a white solid.
MS (ESI) m / z: 497 (M + 1) ^<+> .
HRMS (EI) m / z: 496.2495 (Calcd for C 30 H 32 N 4 O 3 496.2475).
¹ H-NMR (CDCl ₃ ) δ: 1.49 (9H, s), 2.08-2.15 (1H, m), 2.55-2.65 (1H, m), 2.68 (3H , S), 2.83 (2H, t, J = 7.8 Hz), 3.10-3.20 (3H, m), 3.41 (2H, t, J = 6.8 Hz), 3.70 (1H, dd, J = 6.1, 9.2 Hz), 4.45-4.60 (1H, br), 5.03 (1H, d, J = 6.8 Hz), 7.19-72. 6 (3H, m), 7.30-7.35 (2H, m), 7.38 (1H, dd, J = 4.9, 7.6 Hz), 8.08 (1H, dd, J = 1) .5, 7.6 Hz), 8.46 (1H, dd, J = 1.5, 4.9 Hz).
IR (ATR): 3363, 2225, 1705, 1392, 1165, 750 cm ⁻¹ .

[Example 35]
5-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -7-methyl-6- (2-phenylethyl) [1] benzofuro [2,3-b] pyridine-8-carbonitrile ( # 35)
tert-butyl {(3S) -1- [8-cyano-7-methyl-6- (2-phenylethyl) [1] benzofuro [2,3-b] pyridin-5-yl] pyrrolidin-3-yl} Carbamate (I-129) (75 mg, 0.15 mmol) was dissolved in 1,4-dioxane solution (2 ml) of 4N hydrochloric acid and stirred at room temperature for 6 hours. After evaporating the solvent under reduced pressure, tetrahydrofuran (10 ml) was added to the residue. This was concentrated under reduced pressure. This operation was repeated twice more. The obtained residue was dried well under reduced pressure and dissolved in methanol (3 ml). Triethylamine (23 μl, 0.17 mmol) was added to this solution at room temperature, and the mixture was stirred at the same temperature for 10 minutes. Then acetic acid (54 μl, 0.90 mmol), 37% formaldehyde solution (73 μl, 0.90 mmol) and sodium cyanoborohydride (34 mg, 0.54 mmol) were added. After stirring at the same temperature for 22 hours, chloroform and 1N aqueous sodium hydroxide solution were added to the reaction solution. After vigorous stirring at room temperature for 10 minutes, the organic layer was separated and the aqueous layer was further extracted with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using preparative TLC (chloroform: methanol = 93: 7, v / v) to give 48 mg (74%) of the title compound as a white solid. Got as.

MS (ESI) m / z: 425 (M + 1) ^<+> .
HRMS (EI) m / z: 424.2293 (Calcd for C 27 H 28 N 4 O 424.2263).
¹ H-NMR (CDCl ₃ ) δ: 2.13-2.25 (1H, m), 2.34 (6H, s), 2.35-2.45 (1H, m), 2.69 (3H , S), 2.78-2.88 (2H, m), 3.00-3.20 (3H, m), 3.39-3.50 (4H, m), 7, 19-7.26. (3H, m), 7.33 (2H, t, J = 7.6 Hz), 7.42 (1H, dd, J = 4.9, 7.6 Hz), 8.27 (1H, dd, J = 1.7, 7.6 Hz), 8.47 (1H, dd, J = 1.7, 4.9 Hz).
IR (ATR): 2224, 1452, 1389, 1348, 1151, 1014, 908, 779, 746, 696 cm ⁻¹ .
Anal. _{Calcd for C 27 H 28 N 4} O · 0.25H 2 O: C, 75.58; H, 6.70; N, 13.06. Found: C, 75.29; H, 6.65; N, 12.91.

[Reference Example 130]
5-Methoxy-7-methyl-6-[(E) -2-phenylvinyl] [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-130)
5-Fluoro-7-methyl-6-[(E) -2-phenylvinyl] [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-127) (131 mg, 0.40 mmol). Dissolved in methanol (2.6 ml) and N, N-dimethylformamide (1.3 ml), potassium carbonate (110 mg, 0.80 mmol) was added at room temperature. The suspension was stirred at 70 ° C. for 4 hours and then cooled to room temperature. The reaction mixture was fractionated with ethyl acetate and saturated brine. The aqueous layer was further extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using medium pressure liquid chromatography (eluent: chloroform) to give 110 mg (81%) of the title compound as a white solid.
MS (ESI) m / z: 341 (M + 1) ⁺ .
HRMS (EI) m / z: 340.1192 (Calcd for C 22 H 16 N 2 O 2 340.1202).
¹ H-NMR (CDCl ₃ ) δ: 2.73 (3H, s), 4.00 (3H, s), 7.07 (1H, d, J = 16.6 Hz), 7.12 (1H, d , J = 16.6 Hz), 7.31-7.37 (1H, m), 7.39-7.45 (3H, m), 7.56-7.59 (2H, m).
IR (ATR): 2224, 1577, 1389, 1302, 1230, 1117, 1009, 968, 779, 750 cm ⁻¹ .

[Reference Example 131]
8-cyano-7-methyl-6-[(E) -2-phenylvinyl] [1] benzofuro [2,3-b] pyridin-5-yl trifluoromethanesulfonate (I-131)
5-methoxy-7-methyl-6-[(E) -2-phenylvinyl] [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-130) (110 mg, 0.32 mmol). Dissolved in N, N-dimethylacetamide (2.2 ml), sodium acetate (80 mg, 0.97 mmol) was added at room temperature. The suspension was stirred at 130 ° C. for 21 hours. After cooling to room temperature, the reaction mixture was added to 1N aqueous hydrochloric acid under ice cooling. The mixture was stirred at the same temperature for 10 minutes, and the solid was collected by filtration while washing with water. After sufficiently draining water, the solid was dried under reduced pressure. This was dissolved in pyridine (2 ml), and 4- (dimethylamino) pyridine (7 mg, 0.06 mmol) and trifluoromethanesulfonic anhydride (148 μl, 0.87 mmol) were added at 0 ° C. After stirring at room temperature for 24 hours, the reaction mixture was fractionated with ethyl acetate and saturated brine. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 9: 1, v / v) to give the title compound. 83 mg (56%) were obtained as a white solid.
MS (ESI) m / z: 459 (M + 1) ^<+> .
HRMS (EI) m / z: 458.0549 (Calcd for C 22 H 13 F 3 N 2 O 4 S 458.0548).
¹ H-NMR (CDCl ₃ ) δ: 2.79 (3H, s), 6.86 (1H, d, J = 16.6 Hz), 6.98 (1H, d, J = 16.6 Hz), 7 .39-7.46 (3H, m), 7.51 (1H, dd, J = 4.9, 7.6 Hz), 7.52-7.58 (2H, m), 8.54 (1H, dd, J = 1.2, 7.6 Hz), 8.60 (1H, dd, J = 1.2, 4.9 Hz).
IR (ATR): 2233, 1593, 1398, 1219, 1134, 760 cm ⁻¹ .

[Reference Example 132]
tert-Butyl [3- (8-cyano-7-methyl-6-[(E) -2-phenylvinyl] [1] benzofuro [2,3-b] pyridin-5-yl) cyclopent-2-ene- 1-yl] carbamate (I-132)
8-cyano-7-methyl-6-[(E) -2-phenylvinyl] [1] benzofuro [2,3-b] pyridin-5-yl trifluoromethanesulfonate (I-131) (400 mg, 0.87 mmol) ) And tert-butyl (3-tri-n-butylstannylcyclopent-2-en-1-yl) carbamate (618 mg, 1.31 mmol) in 1,4-dioxane (8 ml) and salified at room temperature. Lithium (111 mg, 2.62 mmol), 2,6-ditert-butyl-p-cresol (4 mg, 0.02 mmol), dichlorobis (triphenylphosphine) palladium (II) (92 mg, 0.13 mmol) were added. The mixture was stirred at 110 ° C. for 12 hours under a nitrogen stream, and then cooled to room temperature. The insoluble material was filtered off while washing with ethyl acetate, and the filtrate was fractionated with ethyl acetate and saturated brine. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified using medium pressure liquid chromatography (eluent: n-hexane: ethyl acetate = 4: 1 → 2: 1, v / v), and the title was obtained as a crude product. 287 mg of compound was obtained. This was dissolved in dichloromethane (5.7 ml), and water (0.57 ml) and potassium fluoride (381 mg, 6.55 mmol) were added at room temperature. This was stirred vigorously at room temperature for 12 hours. The reaction mixture was fractionated with dichloromethane and saturated brine. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 3: 1, v / v) to give the title compound. 281 mg (66%) was obtained as a colorless gel.
MS (ESI) m / z: 492 (M + 1) ^<+> .
HRMS (FAB) m / z: 492.2311 (Calcd for C 31 H 30 N 3 O 3 492.2287).
¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.75-1.85 (1H, m), 2.52-2.85 (3H, m), 2.70 (3H , S), 4.60-4.80 (1H, br), 4.92-5.08 (1H, br), 6.04 (1H, d, J = 1.7 Hz), 6.71 (1H , D, J = 16.6 Hz), 7.06 (1H, d, J = 16.6 Hz), 7.30-7.38 (2H, m), 7.40-7.44 (2H, m) 7.48-7.52 (2H, m), 8.14 (1H, d, J = 7.6 Hz), 8.45 (1H, dd, J = 1.7, 4.9 Hz).
IR (ATR): 2227, 1699, 196, 1390, 1234, 1163, 748 cm ⁻¹ .

[Example 36]
5- (3-Dimethylaminocyclopent-1-en-1-yl) -7-methyl-6-[(E) -2-phenylvinyl] [1] benzofuro [2,3-b] pyridine-8- Carbonitrile (# 36)
tert-butyl [3- (8-cyano-7-methyl-6-[(E) -2-phenylvinyl] [1] benzofuro [2,3-b] pyridin-5-yl) cyclopent-2-ene- 1-yl] carbamate (I-132) (100 mg, 0.20 mmol) was dissolved in 1,4-dioxane solution (3 ml) of 4N hydrochloric acid and stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and tetrahydrofuran (5 ml) was added to the residue. The solution was concentrated under reduced pressure. This operation was repeated twice. The residue was dried well under reduced pressure, and methanol (4 ml) was added thereto. Triethylamine (31 μl, 0.22 mmol) was added to this solution at room temperature, and the mixture was stirred at the same temperature for 10 minutes. To this solution were added 37% formaldehyde solution (97 μl, 1.20 mmol), acetic acid (71 μl, 1.20 mmol) and sodium cyanoborohydride (46 mg, 0.72 mmol) at room temperature, and the mixture was stirred at the same temperature for 11 hours. Chloroform and 1N aqueous sodium hydroxide solution were added to this suspension, and the mixture was vigorously stirred for 15 minutes. The organic layer was separated and the aqueous layer was further extracted with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off and the solvent was evaporated. The residue obtained was purified using preparative TLC (eluent; chloroform: methanol = 9: 1, v / v) to give 54 mg (63%) of the title compound. Was obtained as a white solid.

MS (ESI) m / z: 420 (M + 1) ⁺ .
HRMS (EI) m / z: 419.1995 (Calcd for C 28 H 25 N 3 O 419.1998).
¹ H-NMR (CDCl ₃ ) δ: 1.95-2.10 (1H, m), 2.15-2.25 (1H, m), 2.30 (6H, s), 2.58-2 .70 (1H, m), 2.73 (3H, s), 2.73-2.82 (1H, m), 3.85-4.5 (1H, br), 6.05 (1H, d) , J = 1.7 Hz), 6.70 (1H, d, J = 16.6 Hz),. 09 (1H, d, J = 16.6 Hz), 7.30-7.35 (2H, m), 7.39 (2H, t, J = 7.1 Hz), 7.47 (2H, t, J = 7.1 Hz), 8.18 (1H, br d, J = 6.1 Hz), 8.46 (1H, dd, J = 1.7, 4.9 Hz).
IR (ATR): 2225, 1390, 775, 754, 698 cm ⁻¹ .
Anal. _{Calcd for C 28 H 25 N 3} O · 0.5H 2 O: C, 78.48; H, 6.12; N, 9.81. Found: C, 78.29; H, 5.87; N, 9.68.

[Reference Example 133]
5-Fluoro-6-formyl-7-methyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-133)
5-Fluoro-7-methyl-6-[(E) -2-phenylvinyl] [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-127) (360 mg, 1.10 mmol). Dissolved in dichloroethane (4 ml) and water (4 ml), ruthenium chloride (11 mg, 0.06 mmol) and sodium metaperiodate (469 mg, 2.20 mmol) were added at room temperature. After stirring at the same temperature for 24 hours, the insoluble material was filtered off while washing with ethyl acetate. The filtrate was washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using medium pressure liquid chromatography (eluent; n-hexane: ethyl acetate = 3: 1, v / v) to give the title compound. 82 mg (29%) were obtained as a white solid.
MS (ESI) m / z: 255 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 3.03 (3H, s), 754 (1H, dd, J = 4.9, 7.6 Hz), 8.44 (1H, dd, J = 1.7, 7.6 Hz), 8.61 (1 H, dd, J = 1.7, 4.9 Hz), 10.64 (1 H, s).

[Reference Example 134]
5-[(3S) -3- (Dimethylamino) pyrrolidin-1-yl] -6-formyl-7-methyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-134)
5-fluoro-6-formyl-7-methyl [1] benzofuro [2,3-b] pyridine-8-carbonitrile (I-133) (51 mg, 0.20 mmol) was dissolved in dimethyl sulfoxide (1 ml), Triethylamine (42 μl, 0.30 mmol) and (3S) -3- (dimethylamino) pyrrolidine (255 μl, 0.30 mmol) were added at room temperature. The reaction solution was stirred at room temperature for 10 hours under a nitrogen stream. This was fractionated with ethyl acetate and saturated brine. The aqueous layer was further extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using preparative TLC (eluent; chloroform: methanol = 9: 1, v / v) to give 55 mg (78%) of the title compound. Was obtained as an orange solid.
MS (ESI) m / z: 349 (M + 1) ^<+> .
HRMS (EI) m / z: 348.1577 (Calcd for C 20 H 20 N 4 O 2 348.1587).
¹ H-NMR (CDCl ₃ ) δ: 2.05 (1H, dq, J = 9.0, 12.3 Hz), 2.28-2.36 (1H, m), 2.29 (6H, s) , 2.88-2.97 (1H, m), 2.90 (3H, s), 3.59 (1H, dd, J = 8.1, 10.5 Hz), 3.70-3.83 ( 3H, m), 7.38 (1H, dd, J = 4.9, 7.8 Hz), 8.18 (1H, dd, J = 1.5, 7.8 Hz), 8.41 (1H, dd) , J = 1.5, 4.9 Hz), 10.23 (1H, s).
IR (ATR): 2225, 1678, 1556, 1460, 1383, 1340, 1205, 1142, 1097, 796, 775 cm ⁻¹ .

[Example 37]
Methyl (2E) -3- {8-cyano-5-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -7-methyl [1] benzofuro [2,3-b] pyridine-6- Il} acrylate (# 37)

  Trimethylphosphonoacetate (70 μl, 0.43 mmol) was added to a suspension of sodium hydride (55% in mineral oil; 18 mg, 0.41 mmol) in tetrahydrofuran (1 ml) at 0 ° C. After stirring at the same temperature for 10 minutes, 5-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -6-formyl-7-methyl [1] benzofuro [2,3-b] pyridine-8 A solution of carbonitrile (I-134) (68 mg, 0.20 mmol) dissolved in tetrahydrofuran (2 ml) was added dropwise. After stirring at the same temperature for 1.5 hours, the mixture was stirred at room temperature for 7 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution at 0 ° C. This solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified using preparative TLC (eluent; chloroform: methanol = 9: 1, v / v) to give 67 mg (85%) of the title compound. Was obtained as a yellow solid.

MS (ESI) m / z: 405 (M + 1) ^<+> .
HRMS (EI) m / z: 404.1847 (Calcd for C 23 H 24 N 4 O 3 404.1848).
¹ H-NMR (CDCl ₃ ) δ: 2.06 (1H, dq, J = 8.8, 12.2 Hz), 2.30-2.40 (1H, m), 2.33 (6H, s) 2.96 (1H, dq, J = 7.1, 8.1 Hz), 3.40 (1H, dd, J = 8.1, 9.5 Hz), 3.50-3.60 (3H, m ), 3.87 (H, s), 6.05 (1H, d, J = 16.1 Hz), 7.41 (1H, dd, J = 4.9, 7.6 Hz), 7.83 (1H) , D, J = 16.1 Hz), 8.15 (1H, dd, J = 1.5, 7.6 Hz), 8.43 (1H, dd, J = 1.5, 4.9 Hz).
IR (ATR): 2218, 1711, 1464, 1439, 1392, 1311, 1275, 1169, 1142, 983, 783 cm ⁻¹ .
Anal. _{Calcd for C 23 H 24 N 4} O 3 · 0.25H 2 O: C, 67.55; H, 6.04; N, 13.70. Found: C, 67.20; H, 5.89; N, 13.85.

[Reference Example 135]
6-Fluoro-5- (3-fluoropyridin-4-yl) -4-methoxy-2-methylbiphenyl-3-carbonitrile (I-135)
5-Bromo-6-fluoro-4-methoxy-2-methylbiphenyl-3-carbonitrile (I-91) (365 mg, 1.14 mmol), 3-fluoro-4- (4,4,5,5-tetra Toluene (7.3 ml) was added to methyl-1,3,2-dioxaborolan-2-yl) pyridine (509 mg, 5.17 mmol) and cesium carbonate (744 mg, 2.28 mmol), and tetrakis ( Triphenylphosphine) palladium (0) (132 mg, 0.11 mmol) was added, and the mixture was heated to reflux for 35 hours. The mixture was cooled to room temperature, insolubles were removed by filtration with ethyl acetate, and the filtrate was fractionated with ethyl acetate and saturated brine. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating the solvent under reduced pressure was subjected to silica gel column chromatography, eluting with a mixed solvent of n-hexane-ethyl acetate (4: 1, v / v) to obtain 376 mg (98%) of the title compound. Obtained as a yellow clear oil.
MS (ESI) m / z: 337 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.41 (3H, s), 3.85 (3H, s), 7.24-7.36 (3H, m), 7.43-7.49 (2H M), 7.57-7.63 (1H, m), 8.52 (1H, d, J = 4.4 Hz), 8.61 (1H, s).

[Reference Example 136]
5-Fluoro-7-methyl-6-phenyl [1] benzofuro [2,3-c] pyridine-8-carbonitrile (I-136)
6-Fluoro-5- (3-fluoropyridin-4-yl) -4-methoxy-2-methylbiphenyl-3-carbonitrile (I-135) (100 mg, 0.30 mmol) dissolved in dimethyl sulfoxide (4 ml) Then, triethylamine (125 μl, 0.89 mmol) was added at room temperature under a nitrogen stream. The temperature was gradually raised from room temperature to 120 ° C., and the mixture was stirred at the same temperature for 17.5 hours. After cooling to room temperature, the reaction mixture was fractionated with ethyl acetate and saturated brine. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The product was subjected to silica gel column chromatography and eluted with a mixed solvent of n-hexane-ethyl acetate (3: 1, v / v) to obtain 24 mg (27%) of the title compound as a yellowish white solid.
MS (ESI) m / z: 303 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.53 (3H, s), 7.25-7.31 (3H, m), 7.49-7.55 (3H, m), 7.94 (1H , D, J = 5.1 Hz), 8.70 (1H, d, J = 5.1 Hz), 9.12 (1H, s).

[Example 38]
5-[(3S) -3- (Dimethylamino) pyrrolidin-1-yl] -7-methyl-6-phenyl [1] benzofuro [2,3-c] pyridine-8-carbonitrile (# 38)
Under a nitrogen atmosphere, 5-fluoro-7-methyl-6-phenyl [1] benzofuro [2,3-c] pyridine-8-carbonitrile (I-136) (302 mg, 1.00 mmol) was added to dimethyl sulfoxide (3. 0 ml), triethylamine (351 μl, 2.50 mmol) and (3S) -3- (dimethylamino) pyrrolidine (165 μl, 1.30 mmol) were added, and the mixture was stirred at 90 ° C. for 5 hours. After cooling to room temperature, ethyl acetate and diethyl ether were added, washed with a 1N aqueous sodium hydroxide solution, and the organic layer was extracted with a 1N aqueous hydrochloric acid solution. The obtained aqueous layer was made basic by adding a 1N aqueous sodium hydroxide solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was recrystallized with a mixed solvent of ethyl acetate-diisopropyl ether to obtain 282 mg (71%) of the title compound as a light brown solid.

mp: 201-203 ° C. (dec.)
MS (ESI) m / z: 397 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 1.73 (1H, brs), 2.08 (1H, brs), 2.15 (6H, s), 2.35 (3H, s), 2. 63 (1H, br s), 2.73 (1 H, br s), 3.00-3.15 (3H, m), 7.18 (1 H, d, J = 7.8 Hz), 7.21 ( 1H, d, J = 6.6 Hz), 7.42-7.51 (3H, m), 7.71 (1H, d, J = 5.1 Hz), 8.66 (1H, d, J = 5) .4 Hz), 9.07 (1H, s).
IR (ATR): 2225, 1421 cm ⁻¹ .
Anal. _{Calcd for C 25 H 24 N 4} O: C, 75.73; H, 6.10; N, 14.13. Found: C, 75.46; H, 6.03; N, 13.88.

[Reference Example 137]
5- (4-Chloropyridin-3-yl) -6-fluoro-4-methoxy-2-methylbiphenyl-3-carbonitrile (I-137)
5-Bromo-6-fluoro-4-methoxy-2-methylbiphenyl-3-carbonitrile (I-91) (134 mg, 0.42 mmol), 4-chloro-3- (4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl) pyridine (200 mg, 0.84 mmol) and cesium carbonate (272 mg, 0.84 mmol) were suspended in toluene (2.7 ml) and at room temperature under a nitrogen stream. Tetrakis (triphenylphosphine) palladium (0) (48 mg, 0.04 mmol) was added, and the mixture was heated to reflux for 15 hours. Since the reaction was not completed, tetrakis (triphenylphosphine) palladium (0) (24 mg, 0.02 mmol) was added, and the mixture was heated to reflux for 3 hours. The mixture was allowed to cool and insolubles were removed by filtration through Celite while washing with ethyl acetate, and the filtrate was fractionated with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by concentrating the solvent under reduced pressure was subjected to silica gel column chromatography, eluting with a mixed solvent of n-hexane-ethyl acetate (4: 1, v / v) to give 103 mg (70%) of the title compound. Obtained as a yellow clear oil.
MS (ESI) m / z: 353 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.42 (3H, s), 3.79 (3H, s), 7.25-7.49 (4H, m), 8.54 (1H, s), 8.57 (1H, d, J = 5.4 Hz).

[Reference Example 138]
9-Fluoro-7-methyl-8-phenyl [1] benzfuro [3,2-c] pyridine-6-carbonitrile (I-138)
5- (4-Chloropyridin-3-yl) -6-fluoro-4-methoxy-2-methylbiphenyl-3-carbonitrile (I-137) (81 mg, 0.23 mmol) was added to dimethyl sulfoxide (0.8 ml). And triethylamine (97 μl, 0.69 mmol) was added at room temperature under a nitrogen stream. The temperature was gradually raised from room temperature to 120 ° C., and the mixture was stirred at the same temperature for 3 hours. After cooling to room temperature, the reaction mixture was fractionated with ethyl acetate and dilute aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The product was subjected to silica gel column chromatography and eluted with a mixed solvent of n-hexane-ethyl acetate (2: 1, v / v) to obtain 48 mg (68%) of the title compound as a white solid.
MS (ESI) m / z: 303 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.52 (3H, s), 7.30 (2H, dd, J = 1.7, 8.1 Hz), 7.47-7.56 (3H, m) 7.66 (1 H, d, J = 5.9 Hz), 8.78 (1 H, d, J = 5.9 Hz), 9.30 (1 H, s).

[Example 39]
9-[(3S) -3- (Dimethylamino) pyrrolidin-1-yl] -7-methyl-8-phenyl [1] benzofuro [3,2-c] pyridine-6-carbonitrile (# 39)
Under a nitrogen atmosphere, 9-fluoro-7-methyl-8-phenyl [1] benzfuro [3,2-c] pyridine-6-carbonitrile (I-138) (160 mg, 0.53 mmol) was added to dimethyl sulfoxide (3. 2 ml), triethylamine (178 μl, 1.27 mmol) and (3S) -3- (dimethylamino) pyrrolidine (81 μl, 0.64 mmol) were added, and the mixture was stirred at 80 ° C. for 16 hours. Since the reaction was not completed, (3S) -3-dimethylaminopyrrolidine (14 μl, 0.11 mmol) was further added and stirred at 80 ° C. for 6 hours. The mixture was allowed to cool, dichloromethane was added, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by preparative TLC (chloroform: methanol = 20: 1, v / v). 1N Hydrochloric acid ethanol solution (1.1 ml) was added to the resulting crude ethanol solution (2 ml), and the mixture was stirred at room temperature. The solvent was concentrated and evaporated under reduced pressure, and the resulting residue was subjected to preparative TLC and eluted with a mixed solvent of chloroform-methanol (20: 1, v / v, containing 1% triethylamine). It was insufficient. Therefore, the obtained crude product was dissolved in ethyl acetate and extracted with 1N hydrochloric acid aqueous solution. The aqueous layer was made alkaline with a 1N aqueous sodium hydroxide solution, extracted with dichloromethane, and dried over anhydrous sodium sulfate. The obtained organic layer was concentrated under reduced pressure and recrystallized with a mixed solvent of n-hexane-ethyl acetate-diisopropyl ether to obtain 41 mg (19%) of the title compound as a white solid.

mp: 168-170 ° C
MS (ESI) m / z: 397 (M + 1) ⁺ .
¹ H-NMR (DMSO-d ₆ ) δ: 1.59-1.68 (1H, m), 1.95-2.01 (1H, m), 2.05 (6H, s), 2.25 (3H, s), 2.62-2.69 (1H, m), 2.73 (1H, dd, J = 7.6, 8.5 Hz), 2.97-3.07 (3H, m) 7.28 (2H, dd, J = 7.8, 13.9 Hz), 7.44-7.54 (3H, m), 7.89 (1H, d, J = 5.6 Hz), 8. 70 (1H, d, J = 5.6 Hz), 9.03 (1H, s).
IR (ATR): 2222, 1587, 1431 cm ⁻¹ .
Anal. _{Calcd for C 25 H 24 N 4} O: C, 75.73; H, 6.10; N, 14.13. Found: C, 75.35; H, 6.04; N, 14.00.

[Reference Example 139]
5-Bromo-4-fluoro-2-nitrobenzonitrile (I-139)
3-Bromo-4-fluorobenzonitrile (25 g, 0.125 mmol) was dissolved in concentrated sulfuric acid (200 ml), and fuming nitric acid was added dropwise at 0 ° C. over 1 hour. After stirring at the same temperature for 30 minutes, the temperature was raised to room temperature over 1.5 hours. This was slowly opened on ice. The resulting precipitate was collected by filtration while washing with water, and dried under reduced pressure. The collected yellow powder was fractionated with chloroform and 1N aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was dried well under reduced pressure to obtain 14.7 g (48%) of the title compound as a yellow powder.
¹ H-NMR (CDCl ₃ ) δ: 8.11 (1H, d, J = 7.3 Hz), 8.16 (1H, d, J = 6.4 Hz).

[Reference Example 140]
6-Fluoro-4-nitrobiphenyl-3-carbonitrile (I-140)
5-Bromo-4-fluoro-2-nitrobenzonitrile (I-139) (9.1 g, 37.14 mmol) was dissolved in tetrahydrofuran (270 ml) and phenylboronic acid (9.06 g, 74.28 mmol) was dissolved at room temperature. ), Tripotassium phosphate (15.77 g, 74.28 mmol) and tetrakis (triphenylphosphine) palladium (0) (2.15 g, 1.86 mmol) were added. The mixture was stirred at 75 ° C. for 48 hours under a nitrogen stream, and then cooled to room temperature. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was fractionated with chloroform and saturated aqueous ammonium chloride. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the residue obtained by evaporating the solvent was purified by column chromatography using silica gel (eluent; chloroform: hexane = 1: 1, v / v) to give 7.75 g of the title compound ( 86%) as a brown powder.
¹ H-NMR (CDCl ₃ ) δ: 7.52-7.60 (5H, m), 8.02 (1H, d, J = 7.1 Hz), 8.17 (1H, d, J = 9. 5 Hz).

[Reference Example 141]
6-[(3S) -3- (Dimethylamino) pyrrolidin-1-yl] -4-nitrobiphenyl-3-carbonitrile (I-141)
6-Fluoro-4-nitrobiphenyl-3-carbonitrile (I-140) (6.0 g, 24.77 mmol) was dissolved in dimethyl sulfoxide (60 ml), and triethylamine (6.9 ml, 49.54 mmol) was dissolved at room temperature. And (3S) -3- (dimethylamino) pyrrolidine (3.77 ml, 29.73 mmol) were added. After stirring at the same temperature for 19 hours, the reaction solution was fractionated with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent was evaporated. The residue obtained was purified by column chromatography using silica gel (eluent; chloroform: methanol = 95: 5, v / v), and 7.90 g of the title compound ( 95%) as an orange powder.
HRMS (EI) m / z: 322.1428 (Calcd for C 18 H 18 N 4 O 2 322.1428).
¹ H-NMR (CDCl ₃ ) δ: 1.43 (1H, br), 1.72-1.81 (1H, m), 1.99-2.08 (1H, m), 2.34 (3H , S), 2.81 (1H, dd, J = 3.7, 9.8 Hz), 3.12-3.24 (3H, m), 3.26-3.32 (1H, m), 7 .30-7.33 (2H, m), 7.36-7.44 (3H, m), 7.50 (1H, s), 7.57 (1H, s).
IR (ATR): 3330, 2220, 1608, 1520, 1419, 1336, 901, 827, 754, 702 cm ⁻¹ .

[Reference Example 142]
4-Amino-6-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] biphenyl-3-carbonitrile (I-142)
6-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -4-nitrobiphenyl-3-carbonitrile (I-141) (7.9 g, 23.5 mmol) dissolved in concentrated hydrochloric acid (40 ml) Then, acetic acid (4.0 ml, 70.5 mmol) and methanol (10 ml) were added at room temperature, and then cooled to 0 ° C. to stannous chloride dihydrate (15.9 g, 70.5 mmol). Slowly added. The mixture was stirred at the same temperature for 20 minutes and then at room temperature for 20 minutes. Methanol (30 ml) was added to this suspension at room temperature, and the mixture was stirred at the same temperature for 24 hours. The reaction mixture was fractionated with ethyl acetate and 1N aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the solvent was evaporated. The residue obtained was purified by column chromatography using silica gel (eluent; chloroform: methanol = 95: 5, v / v) to give 6.475 g of the title compound ( 90%) was obtained as a light brown gel.
MS (ESI) m / z: 307 (M + 1) ^<+> .
HRMS (EI) m / z: 306.1841 (Calcd for C 19 H 22 N 4 306.1845).
¹ H-NMR (CDCl ₃ ) δ: 1.60-1.70 (1H, m), 1.93-2.10 (1H, m), 2.12 (6H, s), 2.50-2 .59 (1H, m), 2.82 (1H, t, J = 9.0 Hz), 2.99-3.09 (3H, m), 4.35 (2H, br), 6.04 (1H) , S), 7.11 (1H, s), 7.22-7.34 (5H, m).
IR (ATR): 3359, 2198, 1606, 1477, 1435, 1348, 1157 cm ⁻¹ .

[Reference Example 143]
4-Amino-6-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -5-iodobiphenyl-3-carbonitrile (I-143)
4-amino-6-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] biphenyl-3-carbonitrile (I-142) (75 mg, 0.25 mmol) was dissolved in acetic acid (1 ml), N-iodosuccinimide (66 mg, 0.29 mmol) was added at room temperature. After stirring at the same temperature for 6 hours under a nitrogen stream, the reaction solution was fractionated with chloroform and 1N aqueous sodium hydroxide solution. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The insoluble material was filtered off and the solvent was evaporated. The residue obtained was purified using preparative TLC (eluent; chloroform: methanol = 9: 1, v / v) to give 67 mg (63%) of the title compound. Was obtained as a brown gel.
MS (ESI) m / z: 433 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 1.58-1.70 (1H, m), 1.91-2.01 (1H, m), 2.15 (6H, s), 2.55-2 .65 (1H, m), 2.93 (1H, t, J = 8.3 Hz), 3.10 (2H, dd, J = 4.9, 8.8 Hz), 3.25 (1H, t, J = 8.3 Hz), 4.99 (2H, br s), 7.19-7.42 (6H, m).

[Reference Example 144]
4-Amino-6-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -5- (2-fluoropyridin-3-yl) biphenyl-3-carbonitrile (I-144)
4-Amino-6-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -5-iodobiphenyl 3-carbonitrile (I-143) (75 mg, 0.17 mmol), 2-fluoro-3 -(4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) pyridine (77 mg, 0.35 mmol) and tripotassium phosphate (74 mg, 0.35 mmol) were added to N, N -Dissolved in dimethylformamide (3 ml) and added tetrakis (triphenylphosphine) palladium (0) (20 mg, 0.02 mmol) at room temperature. The mixture was stirred at 90 ° C. for 12 hours under a nitrogen stream and then cooled to room temperature. The reaction solution was fractionated with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified using preparative TLC (eluent: chloroform: methanol = 9: 1, v / v) to obtain 23 mg (33%) of the title compound as a brown gel.
MS (ESI) m / z: 402 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 59-1.71 (1H, m), 1.90-2.01 (6H, m), 2.10-2.90 (6H, m), 4.05 -4.25 (2H, m), 7.10-7.45 (9H, m).

[Example 40]
5-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -6-phenyl-9H-pyrido [2,3-b] indole-8-carbonitrile (# 40)
4-amino-6-[(3S) -3- (dimethylamino) pyrrolidin-1-yl] -5- (2-fluoropyridin-3-yl) biphenyl-3-carbonitrile (I-144) (23 mg, 0.06 mmol) and pyridine hydrochloride (2.5 g) were heated at 200 ° C. for 1.5 hours. The reaction solution was poured into 28% aqueous ammonia when hot. This solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified using preparative TLC (eluent; ethyl acetate: methanol = 95: 5 → 9: 1 → 8: 2, v / v) to give 5 mg (23 of the title compound) %) As a light brown powder.
MS (ESI) m / z: 382 (M + 1) ^<+> .
HRMS (EI) m / z: 381.1965 (Calcd for C 24 H 23 N 5 381.1954).
¹ H-NMR (CDCl ₃ ) δ: 1.80-1.90 (2H, m), 2.20 (6H, s), 2.77 (1H, quint, J = 7.8 Hz), 3.00 (1H, t, J = 8.8 Hz), 3.22-3.35 (3H, m), 7.34-7.50 (6H, m), 7.63 (1H, s), 8.27 (1H, dd, J = 1.2, 7.8 Hz), 8.99 (1H, d, J = 5.1 Hz), 12.62 (1H, br s).
IR (ATR): 2921, 2852, 1726, 1583, 1466, 1392, 1271, 912, 764, 708 cm ⁻¹ .

[Reference Example 145]
Methyl [3- (phenylacetyl) -1-benzofuran-2-yl] acetate (I-145)
Under a nitrogen atmosphere, a solution of methyl (1-benzofuran-2-yl) acetate (2.00 g, 10.52 mmol) and phenylacetyl chloride (2.08 ml, 15.77 mmol) was added to a dichloromethane solution (40 ml). A dichloromethane solution (10 ml) of titanium (IV) chloride (1.73 ml, 15.77 mmol) was added dropwise. After stirring at the same temperature for 15 hours, ice water was added to the reaction solution, extracted with chloroform, neutralized with saturated aqueous sodium hydrogen carbonate solution, and washed with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and eluted with a mixed solvent of n-hexane-ethyl acetate (10: 1, v / v) to give 2.56 g (79%) of the title compound as a yellow oil. Obtained.
MS (ESI) m / z: 309 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 3.71 (3H, s), 4.24 (2H, s), 4.35 (2H, s), 7.24-7.40 (7H, m), 7.53-7.55 (1H, m), 7.93-7.95 (1H, m).

[Reference Example 146]
Methyl 1-methoxy-3-methyl-2-phenyldibenzo [b, d] furan-4-carboxylate (I-146)
Methyl [3- (phenylacetyl) -1-benzofuran-2-yl] acetate (I-145) (1.89 g, 6.11 mmol) is dissolved in N, N-dimethylacetamide dimethyl acetal (19 ml) and heated for 1 hour. Refluxed. After allowing to cool, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. Elution with a mixed solvent of n-hexane-ethyl acetate (8: 1, v / v) gave 1.23 g (58%) of the title compound as yellow crystals.
mp: 142-143 ° C.
MS (ESI) m / z: 347 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.29 (3H, s), 3.61 (3H, s), 4.06 (3H, s), 7.26-7.50 (7H, br), 7.62 (1H, d, J = 8.3 Hz), 8.03 (1H, d, J = 7.6 Hz).
IR (ATR): 1709, 1232, 1065 cm ⁻¹ .
Anal. _{Calcd for C 22 H 18 O 4} : C, 76.29; H, 5.24. Found: C, 75.86; H, 5.16.

[Reference Example 147]
1-methoxy-3-methyl-2-phenyldibenzo [b, d] furan-4-carboxylic acid (I-147)
Methyl 1-methoxy-3-methyl-2-phenyldibenzo [b, d] furan-4-carboxylate (I-146) (996 mg, 2.88 mmol) is suspended in methanol (20 ml) and 1N hydroxylated. An aqueous sodium solution (8.70 ml, 8.70 mmol) was added, and the mixture was heated to reflux for 19 hours. The reaction solution was returned to room temperature, adjusted to pH = 5 with 1N aqueous hydrochloric acid solution, and the solvent was evaporated under reduced pressure. Water was added to the obtained residue, and the precipitated solid was collected by filtration, washed with water and n-hexane, and dried under reduced pressure to obtain 909 mg (95%) of the title compound as a white solid.
MS (ESI) m / z: 333 (M + 1) ^<+> .
¹ H-NMR (DMSO-d ₆ ) δ: 2.13 (3H, s), 3.55 (3H, s), 7.29 (1H, d, J = 6.9 Hz), 7.39-7 .54 (5H, m), 7.72 (1H, d, J = 8.3 Hz), 7.99 (1H, d, J = 7.6 Hz).

[Reference Example 148]
1-methoxy-3-methyl-2-phenyldibenzo [b, d] furan-4-carboxamide (I-148)
Under a nitrogen atmosphere, 1-methoxy-3-methyl-2-phenyldibenzo [b, d] furan-4-carboxylic acid (I-147) (700 mg, 2.11 mmol) was suspended in dichloromethane (7 ml) and iced. Under cooling, catalytic amounts of N, N-dimethylformamide (3 drops) and oxalyl chloride (289 μl, 3.37 mmol) were added dropwise, and the mixture was heated to reflux in an oil bath at 40 ° C. for 3 hours. The reaction solvent was evaporated under reduced pressure, ethyl acetate (7 ml) was added to the obtained residue, and 0.5N ammonia 1,4-dioxane solution (12.6 ml, 6.32 mmol) was added dropwise under ice cooling. And stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from n-hexane-ethyl acetate to obtain 528 mg (76%) of the title compound as a white solid.
MS (ESI) m / z: 332 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.37 (3H, s), 3.60 (3H, s), 6.03 (1H, br), 6.48 (1H, br), 7.24- 7.50 (7H, m), 7.60 (1H, d, J = 8.3 Hz), 8.04 (1H, d, J = 7.1 Hz).

[Reference Example 149]
1-hydroxy-3-methyl-2-phenyldibenzo [b, d] furan-4-carboxamide (I-149)
1-methoxy-3-methyl-2-phenyldibenzo [b, d] furan-4-carboxamide (I-148) (527 mg, 1.59 mmol) was dissolved in 1-dodecanethiol (5 ml) under a nitrogen atmosphere; A 1-dodecanethiol solution (5 ml) of aluminum (III) chloride (636 mg, 4.77 mmol) was added dropwise under ice cooling, and the mixture was heated and stirred at 50 ° C. for 1.5 hours. The reaction mixture was extracted with ethyl acetate and washed with 1N aqueous hydrochloric acid and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. N-Hexane was added to the obtained residue, and the precipitate was collected by filtration to obtain 485 mg (96%) of the title compound as a white solid.
MS (ESI) m / z: 318 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 2.40 (3H, s), 5.11 (1H, s), 5.93 (1H, br), 6.69 (1H, br), 7.26- 7.60 (8H, m), 8.08 (1H, d, J = 7.3 Hz).

[Reference Example 150]
4-Cyano-3-methyl-2-phenyldibenzo [b, d] furan-1-yl trifluoromethanesulfonate (I-150)
Under a nitrogen atmosphere, 1-hydroxy-3-methyl-2-phenyldibenzo [b, d] furan-4-carboxamide (I-149) (382 mg, 1.20 mmol) and a catalytic amount of 4- (dimethylamino) pyridine ( 7.3 mg, 5 mol%) was dissolved in pyridine (3.8 ml), trifluoromethanesulfonic anhydride (809 μl, 4.81 mmol) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was extracted with ethyl acetate and washed with 1N aqueous hydrochloric acid and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from n-hexane-ethyl acetate to obtain 405 mg (78%) of the title compound as a white solid.
MS (FAB) m / z: 432 (M + 1) ⁺ .
¹ H-NMR (CDCl ₃ ) δ: 2.50 (3H, s), 7.30 (2H, dd, J = 2.2, 7.6 Hz), 7.46-7.54 (4H, m) 7.62 (1H, t, J = 7.4 Hz), 7.73 (1H, d, J = 8.3 Hz), 8.25 (1H, d, J = 8.1 Hz).
IR (ATR): 2231 cm ⁻¹ .

[Example 41]
1-[(3S) -3- (dimethylamino) pyrrolidinyl] -3-methyl-2-phenyldibenzo [b, d] furan-4-carbonitrile (# 41)
Under nitrogen atmosphere, bis (dibenzylideneacetone) palladium (0) (5.0 mg, 8.70 μmol), diphenylphosphinoferrocene (16 mg, 29 μmol), sodium tert-butoxide (200 mg, 2.09 mmol) in toluene (18 ml) (3S) -3- (dimethylamino) pyrrolidine (0.21 ml, 1.63 mmol) was added dropwise at room temperature. The temperature was raised to 80 ° C. and stirred for 10 minutes. The reaction solution was returned to room temperature and 4-cyano-3-methyl-2-phenyldibenzo [b, d] furan-1-yl trifluoromethanesulfonate (I-150) (500 mg, 1) suspended in toluene (5 ml). .16 mmol) was slowly added dropwise, the temperature was raised again to 80 ° C., and the mixture was stirred for 24 hours. The reaction solution was returned to room temperature, and the insoluble material was removed by filtration through celite. The filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. Elution with a mixed solvent of n-hexane-ethyl acetate (30: 1, v / v) gave the title compound but it did not solidify, so it was dissolved in ethanol (5 ml), and 4N hydrochloric acid 1,4-dioxane solution (2.50 ml) was added and stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, azeotroped with ethanol and benzene, the obtained residue was dissolved in a small amount of chloroform-methanol, recrystallized with n-hexane-ethyl acetate, and 142 mg of the title compound ( 26%) as a white solid.

mp: 170-172 ° C.
MS (FAB) m / z: 396 (M + 1) ^<+> .
¹ H-NMR (DMSO-d ₆ ) δ: 1.70-1.73 (1H, m), 2.06-2.13 (1H, m), 2.13 (6H, s), 2.32 (3H, s), 2.63-2.69 (2H, m), 3.02-3.06 (1H, m), 3.13-3.22 (2H, m), 7.18-7 .22 (2H, m), 7.39-7.52 (1H, m), 7.67 (1H, d, J = 8.1 Hz), 7.79 (1H, d, J = 7.8 Hz) .
IR (ATR): 2459, 2224, 1593, 1434 cm ⁻¹ .
Anal. _{Calcd for C 26 H 25 N 3} O · HCl · 2H 2 O: C, 66.73; H, 6.46; N, 8.98; Cl, 7.58. Found: C, 66.46; H, 6.00; N, 8.94; Cl, 8.08.

[Example 42]
1- (3-Aminocyclopent-1-en-1-yl) -3-methyl-2-phenyldibenzo [b, d] furan-4-carbonitrile (# 42)
1,4-dioxane solution of 4-cyano-3-methyl-2-phenyldibenzo [b, d] furan-1-yl trifluoromethanesulfonate (I-150) (855 mg, 1.98 mmol) under a nitrogen atmosphere ( 17 ml), lithium chloride (252 mg, 5.95 mmol), 2,6-di-tert-butylcresol (4.3 mg, 0.02 mmol), tert-butyl (3-tri-n-butylstannylcyclopent-2 -En-1-yl) carbamate (1.22 g, 2.58 mmol) and tetrakis (triphenylphosphine) palladium (0) (46 mg, 0.04 mmol) were added, and the mixture was heated to reflux for 48 hours. The reaction solution was returned to room temperature, and the insoluble material was removed by filtration through celite. The obtained filtrate was diluted with ethyl acetate, an aqueous potassium fluoride solution was added, and the mixture was vigorously stirred overnight at room temperature. The reaction solution was extracted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, eluted with a mixed solvent of n-hexane-ethyl acetate (8: 1, v / v), and tert-butyl [3- (4-cyano-3-methyl). 2-Phenyldibenzo [b, d] furan-1-yl) cyclopent-2-en-1-yl] carbamate was obtained as a crude light yellow oil. Subsequently, 4N hydrochloric acid 1,4-dioxane solution (1.4 ml) was added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was partitioned between ethyl acetate and water. The resulting aqueous layer was made alkaline with 1N aqueous sodium hydroxide solution and then re-extracted with chloroform. And washed with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Since it was colored, it was dissolved in a chloroform-methanol mixture, decolorized with activated carbon, and insolubles were filtered off with Celite. The solvent was distilled off under reduced pressure, and the resulting residue was dissolved in a small amount of chloroform and recrystallized from n-hexane-ethyl acetate to obtain 206.9 mg (20%) of the title compound as a pale yellow solid. It was.

mp: 213-215 ° C (dec).
MS (FAB) m / z: 365 (M + 1) ⁺ .
¹ H-NMR (DMSO-d ₆ ) δ: 1.85 (1H, m), 2.18 (2H, m), 2.34 (3H, s), 2.50 (1H, m), 4. 07 (1H, br s), 5.75 (1H, s), 7.22 (2H, d, J = 7.1 Hz), 7.43 (4H, m), 7.61 (1H, t, J = 8.1 Hz), 7.84 (1H, d, J = 8.1 Hz), 8.03 (1H, d, J = 6.8 Hz), 8.25 (2H, br s).
IR (ATR): 2224, 742, 707 cm < ^-1 >.
Anal. _{Calcd for C 25 H 20 N 2} O · 1HCl · 0.75H 2 O: C, 72.46; H, 5.47; N, 6.76; Cl, 8.55. Found: C, 72.64; H, 5.29; N, 6.81; Cl, 8.52.

[Example 43]
1- (3-Dimethylaminocyclopent-1-en-1-yl) -3-methyl-2-phenyldibenzo [b, d] furan-4-carbonitrile (# 43)

  1- (3-aminocyclopent-1-en-1-yl) -3-methyl-2-phenyldibenzo [b, d] furan-4-carbonitrile (# 42) (200 mg, 0.549 mmol) in methanol (4 ml) and 37% aqueous formaldehyde solution (0.9 ml) was added. Acetic acid (113 μl, 1.98 mmol) was added dropwise to the reaction solution in which sodium cyanoborohydride (109 mg, 1.65 mmol) was added and suspended in small portions, and the mixture was stirred at room temperature for 19 hours. 1N Aqueous sodium hydroxide solution (0.12 ml) was added, and the reaction solvent was concentrated under reduced pressure. The obtained residue was diluted with chloroform and washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Subsequently, 1N hydrochloric acid-ethanol solution (5 ml) was added to the residue, and the mixture was stirred at room temperature for 18 hours. The reaction solvent was evaporated under reduced pressure, and the resulting residue was dissolved in a small amount of ethanol and recrystallized from ethyl acetate-diethyl ether to obtain 210 mg (88%) of the title compound as a white solid.

mp: 229-231 ° C (dec).
MS (FAB) m / z: 393 (M + 1) ^<+> .
¹ H-NMR (DMSO-d ₆ ) δ: 1.99 (1H, m), 2.20-2.58 (m, 3H), 2.32 (9H, s), 4.59 (1H, br) s), 5.86 (1H, s), 7.29 (1H, m), 7.44 (4H, m), 7.61 (1H, t, J = 7.6 Hz), 7.77 (1H) M), 7.86 (2H, d, J = 7.8 Hz).
IR (ATR): 2231, 1211 cm ⁻¹ .
Anal. _{Calcd for C 27 H 24 N 2} O · HCl · 0.25H 2 O: C, 74.82; H, 5.93; N, 6.46; Cl, 8.18. Found: C, 74.47; H, 5.79; N, 6.62; Cl, 8.40.

[Reference Example 151]
Methyl 1-methoxy-2-phenyldibenzo [b, d] furan-4-carboxylate (I-151)
Methyl [3- (phenylacetyl) -1-benzofuran-2-yl] acetate (I-145) (2.80 g, 9.06 mmol) is dissolved in N, N-dimethylformamide dimethyl acetal (6 ml) and heated for 24 hours. Refluxed. The mixture was allowed to cool, diluted with ethyl acetate, and washed with 1N aqueous hydrochloric acid and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from n-hexane-ethyl acetate to obtain 2.06 g (68%) of the title compound as a light brown solid.
MS (ESI) m / z: 333 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 3.69 (3H, s), 4.04 (3H, s), 7.39-7.42 (2H, m), 7.47 (2H, d, J = 7.6 Hz), 7.50 (1H, dt, J = 7.1, 7.3 Hz), 7.64 (2H, dd, J = 0.7, 7.6 Hz), 7.71 (1H, d, J = 8.3 Hz), 8.13 (1H, s), 8.17 (1H, d, J = 7.8 Hz).

[Reference Example 152]
1-methoxy-3-methyl-2-phenyldibenzo [b, d] furan-4-carboxamide (I-152)
Methyl 1-methoxy-2-phenyldibenzo [b, d] furan-4-carboxylate (I-151) (2.06 g, 6.19 mmol) is suspended in methanol (20 ml), and 1N aqueous sodium hydroxide solution is suspended. (13 ml, 13.0 mmol) was added and heated to reflux for 42 hours. The reaction solution was returned to room temperature, adjusted to pH = 5 with 1N aqueous hydrochloric acid solution, and the solvent was evaporated under reduced pressure. Water was added to the obtained residue, and the precipitated solid was collected by filtration, washed with water and n-hexane, and dried under reduced pressure to obtain a white solid. This was suspended in dichloromethane (19 ml), and catalytic amounts of N, N-dimethylformamide (1 drop) and oxalyl chloride (820 μl, 9.55 mmol) were added dropwise under ice-cooling. Heated to reflux for 5 hours. The reaction solvent was evaporated under reduced pressure, 40 ml of ethyl acetate was added to the obtained residue, 28% aqueous ammonia solution (19 ml) was added dropwise under ice cooling, and the mixture was stirred at 0 ° C. to room temperature for 65 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with water and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from n-hexane-ethyl acetate to obtain 1.63 g (83%) of the title compound as a white solid.
MS (ESI) m / z: 318 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 3.69 (3H, s), 6.04 (1H, br), 7.37-7.55 (6H, m), 7.62-7.67 (3H M), 8.20 (1H, d, J = 7.6 Hz), 8.29 (1H, s).

[Reference Example 153]
1-hydroxy-2-phenyldibenzo [b, d] furan-4-carboxamide (I-153)
1-Methoxy-2-phenyldibenzo [b, d] furan-4-carboxamide (I-153) (1.63 g, 5.14 mmol) was dissolved in 1-dodecanethiol (16 ml) under a nitrogen atmosphere and ice-cooled. A solution of aluminum (III) chloride (2.05 g, 15.41 mmol) in 1-dodecanethiol (16 ml) was added dropwise, and the mixture was heated and stirred at 50 ° C. for 1 hour and further at 70 ° C. for 1 hour. The reaction mixture was allowed to cool to room temperature, 1N hydrochloric acid was added, the mixture was extracted with ethyl acetate, and washed with saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from n-hexane-ethyl acetate to obtain 1.51 g (97%) of the title compound as a white solid.
MS (ESI) m / z: 304 (M + 1) ^<+> .
¹ H-NMR (DMSO-d ₆ ) δ: 7.39-7.68 (7H, m), 7.69 (2H, d, J = 7.6 Hz), 7.78 (1H, d, J = 7.8 Hz), 7.83 (1 H, s), 8.24 (1 H, d, J = 7.8 Hz), 10.12 (1 H, s).

[Reference Example 154]
4-cyano-2-phenyldibenzo [b, d] furan-1-yl trifluoromethanesulfonate (I-154)
1-hydroxy-2-phenyldibenzo [b, d] furan-4-carboxamide (I-153) (1.51 g, 4.97 mmol) and a catalytic amount of 4- (dimethylamino) pyridine (30 mg, 5 mol%) was dissolved in pyridine (15 ml), trifluoromethanesulfonic anhydride (2.51 ml, 14.91 mmol) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate and washed with 1N aqueous hydrochloric acid and saturated brine. The obtained organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was recrystallized from n-hexane-ethyl acetate to obtain 1.43 g (69%) of the title compound as a white solid.
MS (FAB) m / z: 459 (M + 1) ^<+> .
¹ H-NMR (CDCl ₃ ) δ: 7.47-7.55 (6H, m), 7.67 (1H, dt, J = 1.2, 8.5 Hz), 7.75 (1H, t, J = 8.5 Hz), 7.83 (1H, s), 8.30 (1H, d, J = 8.1 Hz).

[Example 44]
1-[(3S) -3- (dimethylamino) pyrrolidinyl] -2-phenyldibenzo [b, d] furan-4-carbonitrile (# 44)
Under a nitrogen atmosphere, bis (dibenzylideneacetone) palladium (0) (6.9 mg, 12.0 μmol), diphenylphosphinoferrocene (20 mg, 36.0 μmol) and sodium tert-butoxide (207 mg, 2.16 mmol) were added to toluene (207 mg, 2.16 mmol). (3S) -3- (dimethyl) aminopyrrolidine (0.21 ml, 1.68 mmol) was added dropwise at room temperature. The temperature was raised to 80 ° C. and stirred for 10 minutes. The reaction solution was returned to room temperature, and 4-cyano-2-phenyldibenzo [b, d] furan-1-yltrifluoromethanesulfonate (I-154) (500 mg, 1.20 mmol) suspended in toluene (5 ml) was added. The solution was slowly added dropwise, heated again to 80 ° C. and stirred for 3 hours. The reaction solution was returned to room temperature, and the insoluble material was removed by filtration through celite. The obtained filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. Elution with a mixed solvent of chloroform-methanol (50: 1, v / v) gave the title compound but it did not solidify, so it was dissolved in 1,4-dioxane (5 ml) and dissolved in 4N hydrochloric acid 1,4-dioxane. The solution (0.3 ml) was added and stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, azeotroped with toluene, and the resulting residue was recrystallized with n-hexane-ethyl acetate to obtain 32 mg (6%) of the title compound as a white solid.

mp: 170-172 ° C.
MS (FAB) m / z: 382 (M + 1) ^<+> .
¹ H-NMR (DMSO-d ₆ ) δ: 2.15-2.20 (1H, m), 2.30-2.40 (1H, m), 2.65 (6H, br), 3.11 -3.26 (3H, m), 3.43 (1H, dd, J = 7.8, 10.5 Hz), 3.91 (1H, m), 7.41-7.57 (6H, m) , 7.65 (1H, t, J = 6.8 Hz), 7.72 (1H, s), 7.86 (1H, d, J = 8.0 Hz), 7.92 (1H, d, J = 7.3 Hz).
IR (ATR): 2231, 1435, 1165 cm ⁻¹ .
Anal. _{Calcd for C 25 H 23 N 3} O · 1HCl · 1.5H 2 O: C, 67.48; H, 6.12; N, 9.44; Cl, 7.97. Found: C, 67.44; H, 5.98; N, 8.74; Cl, 8.62.

[Test Example 1]
The antifungal activity of the compound of the present invention was measured by the method described below.
(1) Medium used
YPD20 medium (1% yeast extract, 2% peptone, 20% glucose) was used.
(2) Adjustment of inoculum
Bacteria grown overnight at 30 ° C in Sabouraud dextrose agar are suspended in 0.1% Tween 80-added physiological saline, and concentrated medium (1.33% yeast extract, 2.67% pepton so that the final bacterial concentration is 5 × 10 ³ cells / ml. , 13.33% glucose) to obtain an inoculum.
(3) Preparation of drug dilution plate A weighed specimen was dissolved in dimethyl sulfoxide, and a 2-fold dilution series was prepared using dimethyl sulfoxide. A drug dilution plate was prepared by adding 2 μL of each drug dilution to a flat-bottom 96-well plate into which 48 μL of 40% glucose had been dispensed.
(4) Inoculation and culture of the bacterial solution 150 μL of the bacterial solution prepared in (2) was added to the drug dilution plate prepared in (3), and statically cultured at 37 ° C.
(5) Measurement of antifungal activity (GI ₈₀ value) After 18 to 24 hours of culture, the plate was stirred and the absorbance (600 nm) was measured. Using the absorbance as an index, the minimum drug concentration that inhibits the growth of bacteria in wells with no drug added by 80% or more was calculated as the GI ₈₀ value.
The results are shown in the following table.

  It can be seen that the compounds of the present invention exhibit excellent antifungal activity.

Claims (8)

A compound represented by the following formula (I), a salt thereof, or a hydrate thereof:

[Wherein R ¹ is
Saturated or partially saturated 4- to 8-membered nitrogen-containing heterocyclic group containing 1 or 2 nitrogen atoms (where the nitrogen atom is bonded to the mother nucleus when there is 1 nitrogen atom) It is not a site, and an alkyl group having 1 to 6 carbon atoms may be substituted on the nitrogen atom.)
Or as a basic substituent
(1) an amino group,
(2) an alkylamino group having an alkyl group having 1 to 6 carbon atoms,
(3) Dialkylamino groups having 1 to 6 carbon atoms which may be the same or different
(4) aminomethyl group,
(5) an alkylaminomethyl group having an alkyl group having 1 to 6 carbon atoms, or
(6) a dialkylaminomethyl group having an alkyl group having 1 to 6 carbon atoms, which may be the same or different,
Represents a group selected from the following [a] to [c] substituted:
[A]: a saturated or partially saturated 4- to 8-membered ring containing one or two heteroatoms which may be selected from a heteroatom of the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom A heterocyclic group of
[B]: a 4-membered to 6-membered cyclic hydrocarbon group which may contain a double bond,
[C]:
The following formula:
-X ¹ - (alkyl group having 1 to 6 carbon atoms)
[Wherein, X ¹ represents an oxygen atom, a sulfur atom, —CH ₂ —, or a formula:
-N (-R ¹¹ )-
(Here, R ¹¹ on the nitrogen atom represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or an aralkyl group having 7 to 9 carbon atoms.)
The structure shown by is shown. ]
Represents a group represented by
Here, the heterocyclic group of [a] and the cyclic hydrocarbon group of [b] may have one or more groups that may be selected redundantly from [Substituent group 1];
[Substituent group 1]:
A halogen atom,
Hydroxyl group,
A carboxy group,
An alkyl group having 1 to 6 carbon atoms,
An alkoxy group having 1 to 6 carbon atoms,
An alkylthio group having 1 to 6 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
An alkoxycarbonyl group having 2 to 7 carbon atoms,
6 cycloalkyl groups having 3 carbon atoms,
An aralkyloxy group having 7 to 9 carbon atoms,
An aralkyloxycarbonyl group having 8 to 10 carbon atoms, and the following formula:
^{-C (= O) -N (-R} 12) R 13
(Wherein R ¹² and R ¹³ on the nitrogen atom each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an aryl group having 6 to 10 carbon atoms.)
A group represented by:
R ² is
Hydrogen atom,
A halogen atom,
An alkyl group having 1 to 8 carbon atoms,
An alkenyl group having 2 to 8 carbon atoms,
An alkynyl group having 2 to 8 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms,
A cycloalkenyl group having 5 to 6 carbon atoms,
Monocyclic or bicyclic aryl groups,
A monocyclic or bicyclic heteroaryl group (containing 1 to 4 heteroatoms which may be selected from a heteroatom of the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom), or :
-X ² -R ²¹
[Wherein, X ² represents —C (═O) —, — (CH ₂ ) _n —, —C (═O) —N (—R ²² ) —, or —N (—R ²³ ) —C ( = O)-
n represents any integer of 1 to 3,
R ²¹ is
An alkyl group having 1 to 6 carbon atoms,
A monocyclic or bicyclic aryl group, or a monocyclic or bicyclic heteroaryl group (a heteroatom optionally selected from a heteroatom of the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom) 1 to 4 included.)
Indicate
R ²² and R ²³ each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. ]
Represents a group represented by
These alkyl group, alkenyl group, alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group, and heteroaryl group have one or more groups that may be selected from [Substituent Group 2]. May be;
[Substituent group 2]:
A halogen atom,
An amino group,
Hydroxyl group,
A carboxy group,
An alkyl group having 1 to 6 carbon atoms,
An alkoxy group having 1 to 6 carbon atoms,
An alkylthio group having 1 to 6 carbon atoms,
An aryl group having 6 to 10 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
An alkoxycarbonyl group having 2 to 7 carbon atoms,
A 6 cycloalkyl group having 3 carbon atoms and the following formula:
^{-C (= O) -N (-R} 24) R 25
(In the formula, each of R ²⁴ and R ²⁵ on the nitrogen atom independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an aryl group having 6 to 10 carbon atoms.)
A group represented by:
Here, the amino group of [Substituent group 2] is
An alkyl group having 1 to 6 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms,
An aryl group having 6 to 10 carbon atoms,
An aralkyl group having 7 to 12 carbon atoms,
An aromatic heterocyclic group,
The substituent may have one or two groups selected from the group consisting of an alkylsulfonyl group having 1 to 6 carbon atoms and an arylsulfonyl group having 6 to 10 carbon atoms. In the case where there are two, they may combine with each other to form a cyclic structure;
R ³ is
Hydrogen atom,
A linear or branched alkyl group having 1 to 4 carbon atoms,
A cyclic alkyl group having 3 or 4 carbon atoms,
An alkoxy group having 1 to 4 carbon atoms,
A dialkylamino group having the same or different alkyl chain and a total carbon number of 2 to 4,
A group selected from the group consisting of a trihalogenoalkyl group and an alkoxymethyl group having an alkoxy group having 1 to 3 carbon atoms;
R ⁴ is
Cyano group, following formula:
-COOR ⁴¹ or the following formula:
^{-C (= O) -N (-R} 42) R 43
(In these formulas, R ⁴¹ , R ⁴² and R ⁴³ each independently represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.)
Or R ⁴ and R ³ are integrated to form the following formula (showing —R ⁴ —R ³ —):
^{- (C = Y 2) -Y} 1 - (CH 2) p -
(Wherein Y ¹ represents an oxygen atom, a sulfur atom, N—R ⁴⁴ , or C (—R ⁴⁵ ) R ⁴⁶ , Y ² represents an N—R ⁴⁷ , oxygen atom, or sulfur atom; ⁴⁴ , R ⁴⁵ , R ⁴⁶ , and R ⁴⁷ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and p is an integer 1 or 2.)
May form the structure shown by;
formula:

The structural part containing A in the structure represented by represents a 6-membered aromatic ring optionally having 1, 2 or 3 nitrogen atoms;
R ⁵ represents a hydrogen atom or a group selected from the group of substituents represented by the following [i] to [iv]:
[I]:
A halogen atom,
Hydroxyl group,
A carboxy group,
A linear or branched alkyl group having 1 to 6 carbon atoms,
An alkoxy group having 1 to 6 carbon atoms,
An alkoxycarbonyl group having 2 to 7 carbon atoms and a 6 cycloalkyl group having 3 carbon atoms;
[Ii]:
An amino group,
An alkylamino group having an alkyl group having 1 to 6 carbon atoms,
A dialkylamino group having an alkyl group having 1 to 6 carbon atoms, which may be the same or different, and a 4- to 6-membered saturated nitrogen-containing heterocyclic group having a nitrogen atom as a binding site;
[Iii]:
The following formula:
-C (= O) R ⁵¹
(Wherein R ⁵¹ on the carbon atom is
An alkylamino group having an alkyl group having 1 to 6 carbon atoms,
A dialkylamino group having a C 1-6 alkyl group which may be the same or different,
An alkoxy group having 1 to 6 carbon atoms,
An alkyl (alkoxy) amino group having an alkyl group having 1 to 6 carbon atoms and an alkoxy group having 1 to 6 carbon atoms,
Contains one or two heteroatoms which may be selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and contains a 5-membered or 6-membered saturated cyclic ring bonded to the carbonyl on the nitrogen atom. A nitrogen heterocyclic group,
A 5-membered or 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms which may be selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom,
A dialkylamino group having an alkyl group having 1 to 6 carbon atoms, which may be the same, and 1 to 4 heteroatoms which may be selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom An aromatic heterocyclic substituted alkyl group consisting of a 5-membered or 6-membered aromatic heterocyclic group and an alkylene group having 1 to 3 carbon atoms;
A group selected from the group consisting of )
A group represented by:
[Iv]:
The following formula:
^{-N (-R 52) -C (=} O) R 53
(In the formula, R ⁵² and R ⁵³ each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.)
A group represented by:
Furthermore, the alkyl part in the group of substituent groups [i] to [iv] and the alkyl part of the alkoxy group may have one or more groups which may be selected from [Substituent group 5]. In addition, the aromatic or saturated heterocyclic group and the nitrogen-containing heterocyclic group are groups formed by adding an alkyl group having 1 to 6 carbon atoms as a linker to [Substituent group 5]. May have one or more groups that may be selected;
[Substituent group 5]:
A halogen atom,
An amino group,
Hydroxyl group,
A carboxy group,
An alkoxy group having 1 to 6 carbon atoms,
An alkylthio group having 1 to 6 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
An alkoxycarbonyl group having 2 to 7 carbon atoms,
6 cycloalkyl groups having 3 carbon atoms,
An aralkyloxy group having 7 to 9 carbon atoms,
An aralkyloxycarbonyl group having 8 to 10 carbon atoms, and the following formula:
^{-C (= O) -N (-R} 54) R 55
(In the formula, each of R ⁵⁴ and R ⁵⁵ on the nitrogen atom independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an aryl group having 6 to 10 carbon atoms.)
A group represented by:
Here, the amino group of [Substituent group 5] is
An alkyl group having 1 to 6 carbon atoms,
An acyl group having 2 to 7 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms,
An aryl group having 6 to 10 carbon atoms,
An aralkyl group having 7 to 12 carbon atoms,
An aromatic heterocyclic group,
A group selected from the group consisting of an alkylsulfonyl group having 1 to 6 carbon atoms and an arylsulfonyl group having 6 to 10 carbon atoms, which may have one or two substituents, and further the amino group When there are two substituents, they may be bonded to each other to form a cyclic structure;
X represents an oxygen atom, a sulfur atom, N—R ⁶ , or C (—R ⁷¹ ) R ⁷² ;
R ⁶ , R ⁷¹ and R ⁷² each independently represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. ]  The salt according to claim 1, wherein X is an oxygen atom, or a hydrate thereof.  The pharmaceutical containing the compound of Claim 1, its salt, or those hydrates.  The infectious disease therapeutic agent containing the compound of Claim 1, its salt, or those hydrates.  An antifungal agent comprising the compound according to claim 1, a salt thereof, or a hydrate thereof.  A method for treating an infection using the compound according to claim 1, a salt thereof, or a hydrate thereof.  Use of the compound according to claim 1, a salt thereof, or a hydrate thereof for the treatment of infectious diseases.  Use of the compound according to claim 1, a salt thereof, or a hydrate thereof for the manufacture of a therapeutic agent for infectious diseases.